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Abstract:

Disclosed herein, in certain embodiments, are peptides for use in
inhibiting the interactions of PF4 and RANTES. Further disclosed herein,
are methods for treating an inflammatory disease, disorder, condition, or
symptom. In some embodiments, the method comprises co-administering an
agent that inhibits the interactions of PF4 and RANTES and a second
active agent.

where:X1 is chosen from the group containing lysine, glutamine, arginine,
histidine and asparagine, or an amino acid deletion;X2 is chosen from the
group containing glutamic acid, aspartic acid and glutamine, or an amino
acid deletion;X3 is chosen from the group containing glycine, serine and
alanine;X4 is chosen from the group containing lysine, leucine and
arginine;X5 is chosen from the group containing serine, cysteine, glycine
and threonine;X6 is chosen from the group containing proline and
alanine;X7 is chosen from the group containing asparagine and
glutamine;X8 is chosen from the group containing proline, tyrosine and
glycine;X9 is chosen from the group containing glycine, alanine and
serine;X10 is chosen from the group containing isoleucine, valine and
asparagine;X11 is chosen from the group containing valine, isoleucine and
asparagine;X12 is chosen from the group containing phenylalanine,
tyrosine, isoleucine, valine, leucine and methionine;X13 is chosen from
the group containing isoleucine, valine, leucine, methionine and
phenylalanine;X14 is chosen from the group containing threonine, glycine,
alanine, serine and tyrosine;X15 is chosen from the group containing
arginine, lysine, alanine, glutamine, histidine and asparagine, or an
amino acid deletion.

2. The peptide of claim 1, characterized in that the peptide has an amino
acid sequence SEQ ID NO: 2, as indicated below:
TABLE-US-00033
C-KEYFYTSGKCSNPAVVFVTR-C.

3. The peptide of claim 1, characterized in that the peptide has an amino
acid sequence SEQ ID NO: 3, as indicated below:
TABLE-US-00034
C-KEYFYTSSKCSNLAVVFVTR-C.

4. The peptide of claim 1, characterized in that the peptide has an amino
acid sequence SEQ ID NO: 4, as indicated below:
TABLE-US-00035
C-QEYFYTSSKCSMAAVVFITR-C.

9. A method of treating an inflammatory disease, disorder, condition, or
symptom, comprising administering to an individual in need thereof a
therapeutically-effective amount of agent that inhibits interactions
between RANTES and Platelet Factor 4.

10. The method of claim 9, wherein the active agent specifically binds to
the RANTES interacting domain of PF4.

11. The method of claim 9, wherein the active agent is an isolated peptide
that has the amino acid sequence SEQ ID NO: 1, as indicated below:
TABLE-US-00039
C-X1-X2-YFYTS-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-
X13-X14-X15-C

where:X1 is chosen from the group containing lysine, glutamine, arginine,
histidine and asparagine, or an amino acid deletion;X2 is chosen from the
group containing glutamic acid, aspartic acid and glutamine, or an amino
acid deletion;X3 is chosen from the group containing glycine, serine and
alanine;X4 is chosen from the group containing lysine, leucine and
arginine;X5 is chosen from the group containing serine, cysteine, glycine
and threonine;X6 is chosen from the group containing proline and
alanine;X7 is chosen from the group containing asparagine and
glutamine;X8 is chosen from the group containing proline, tyrosine and
glycine;X9 is chosen from the group containing glycine, alanine and
serine;X10 is chosen from the group containing isoleucine, valine and
asparagine;X11 is chosen from the group containing valine, isoleucine and
asparagine;X12 is chosen from the group containing phenylalanine,
tyrosine, isoleucine, valine, leucine and methionine;X13 is chosen from
the group containing isoleucine, valine, leucine, methionine and
phenylalanine;X14 is chosen from the group containing threonine, glycine,
alanine, serine and tyrosine;X15 is chosen from the group containing
arginine, lysine, alanine, glutamine, histidine and asparagine, or an
amino acid deletion.

12. The method of claim 9, wherein the active agent is an isolated peptide
that has the amino acid sequence SEQ ID NO: 2, as indicated below:
TABLE-US-00040
C-KEYFYTSGKCSNPAVVFVTR-C.

13. The method of claim 9, wherein the active agent is an isolated peptide
that has the amino acid sequence SEQ ID NO: 3, as indicated below:
TABLE-US-00041
C-KEYFYTSSKCSNLAVVFVTR-C.

14. The method of claim 9, wherein the active agent is an isolated peptide
that has the amino acid sequence SEQ ID NO: 4, as indicated below:
TABLE-US-00042
C-QLYFYTSSKCSMAAVVFITR-C.

21. A method of treating a disorder of a cardiovascular system, comprising
co-administering to an individual in need thereof a synergistic
combination of (a) a therapeutically-effective amount of an agent that
inhibits the interaction between RANTES and Platelet Factor 4; and (b) a
second active agent selected from an agent that treats a cardiovascular
disorder.

22. The method of claim 21, wherein administration of the second active
agent partially or fully results in undesired inflammation.

23. The method of claim 21, wherein the second active agent is niacin; a
fibrate; a statin; an apolipoprotein A-1 modulator; an ACAT modulator; a
CETP modulator; a glycoprotein IIb/IIIa modulator; a P2Y12 modulator; an
Lp-PLA2 modulator; an anti-hypertensive; a leukotriene inhibitor; an 5-LO
inhibitor; a FLAP inhibitor; or combinations thereof.

[0002]Inflammatory diseases, disorders, conditions and symptoms are
characterized, in part, by the migration of lymphocytes and monocytes
into the affected tissue. The migration of lymphocytes and monocytes
induces tissue damage and exacerbates inflammatory diseases, disorders,
conditions and symptoms.

[0003]RANTES (also known as CCL5) and PF4 are pro-inflammatory chemokines.
In certain instances, they are secreted by an activated platelet in
response to an inflammation or tissue injury. In certain instances,
RANTES and PF4 induce chemotaxis in nearby leukocytes (e.g. monocytes)
along their gradients.

SUMMARY OF THE INVENTION

[0004]There is a need for new methods of treating inflammatory diseases,
disorders, conditions (e.g., atherosclerosis) and symptoms that do not
interfere with (a) non-inflammatory processes or (b) desired-inflammatory
processes. The inventors have discovered that undesired and harmful
inflammation can be treated by inhibiting the interactions of PF4 and
RANTES. Further, the inventors have discovered that targeting precise
regions of PF4 and RANTES will inhibit the ability of the ligands to bind
to each other and their receptors (thus, preventing undesired
inflammation) without affecting other (e.g., desired and beneficial)
interactions of PF4 and RANTES.

[0005]There is also a need to develop methods and compositions for
treating inflammatory diseases, disorders, conditions that combine (a) a
first agent that inhibits inflammation with (b) a second agent that
otherwise treats an inflammatory disease, disorder, condition but results
(or has been shown to result) in undesired inflammation (e.g., myositis).

[0006]Disclosed herein, in certain embodiments, is an isolated peptide,
its pharmacologically acceptable salts, derivatives, and conjugates,
characterized in that the peptide has an amino acid sequence SEQ ID NO:
1, as indicated below:

where:X1 is chosen from the group containing lysine, glutamine, arginine,
histidine and asparagine, or an amino acid deletion;X2 is chosen from the
group containing glutamic acid, aspartic acid and glutamine, or an amino
acid deletion;X3 is chosen from the group containing glycine, serine and
alanine;X4 is chosen from the group containing lysine, leucine and
arginine;X5 is chosen from the group containing serine, cysteine, glycine
and threonine;X6 is chosen from the group containing proline and
alanine;X7 is chosen from the group containing asparagine and
glutamine;X8 is chosen from the group containing proline, tyrosine and
glycine;X9 is chosen from the group containing glycine, alanine and
serine;X10 is chosen from the group containing isoleucine, valine and
asparagine;X11 is chosen from the group containing valine, isoleucine and
asparagine;X12 is chosen from the group containing phenylalanine,
tyrosine, isoleucine, valine, leucine and methionine;X13 is chosen from
the group containing isoleucine, valine, leucine, methionine and
phenylalanine;X14 is chosen from the group containing threonine, glycine,
alanine, serine and tyrosine;X15 is chosen from the group containing
arginine, lysine, alanine, glutamine, histidine and asparagine, or an
amino acid deletion.

[0014]Disclosed herein, in certain embodiments, is a method of treating an
inflammatory disease, disorder, condition, or symptom, comprising
administering to an individual in need thereof a
therapeutically-effective amount of agent that inhibits interactions
between RANTES and Platelet Factor 4.

[0015]In some embodiments, the active agent specifically binds to the
RANTES interacting domain of PF4. In some embodiments, the active agent
is an isolated peptide that has the amino acid sequence SEQ ID NO: 1, as
indicated below:

where:X1 is chosen from the group containing lysine, glutamine, arginine,
histidine and asparagine, or an amino acid deletion;X2 is chosen from the
group containing glutamic acid, aspartic acid and glutamine, or an amino
acid deletion;X3 is chosen from the group containing glycine, serine and
alanine;X4 is chosen from the group containing lysine, leucine and
arginine;X5 is chosen from the group containing serine, cysteine, glycine
and threonine;X6 is chosen from the group containing proline and
alanine;X7 is chosen from the group containing asparagine and
glutamine;X8 is chosen from the group containing proline, tyrosine and
glycine;X9 is chosen from the group containing glycine, alanine and
serine;X10 is chosen from the group containing isoleucine, valine and
asparagine;X11 is chosen from the group containing valine, isoleucine and
asparagine;X12 is chosen from the group containing phenylalanine,
tyrosine, isoleucine, valine, leucine and methionine;X13 is chosen from
the group containing isoleucine, valine, leucine, methionine and
phenylalanine;X14 is chosen from the group containing threonine, glycine,
alanine, serine and tyrosine;X15 is chosen from the group containing
arginine, lysine, alanine, glutamine, histidine and asparagine, or an
amino acid deletion.

[0016]In some embodiments, the active agent is an isolated peptide that
has the amino acid sequence SEQ ID NO: 2, as indicated below:

TABLE-US-00009
C-KEYFYTSGKCSNPAVVFVTR-C.

[0017]In some embodiments, the active agent is an isolated peptide that
has the amino acid sequence SEQ ID NO: 3, as indicated below:

TABLE-US-00010
C-KEYFYTSSKCSNLAVVFVTR-C.

[0018]In some embodiments, the active agent is an isolated peptide that
has the amino acid sequence SEQ ID NO: 4, as indicated below:

TABLE-US-00011
C-QEYFYTSSKCSMAAVVFITR-C.

[0019]In some embodiments, the active agent is an isolated peptide that
has the amino acid sequence SEQ ID NO: 13, as indicated below:

TABLE-US-00012
C-KEYFYTSSKSSNLAVVFVTR-C. (SEQ ID NO 13)

[0020]In some embodiments, the active agent is an isolated peptide that
has the amino acid sequence SEQ ID NO: 14, as indicated below:

TABLE-US-00013
CSFKGTTVYALSNVRSYSFVKC. (SEQ ID NO 14)

[0021]In some embodiments, the active agent is an isolated peptide that
has the amino acid sequence SEQ ID NO: 15, as indicated below:

[0023]Disclosed herein, in certain embodiments, is a method of treating a
disorder of a cardiovascular system, comprising co-administering to an
individual in need thereof a synergistic combination of (a) a
therapeutically-effective amount of an agent that inhibits the
interaction between RANTES and Platelet Factor 4; and (b) a second active
agent selected from an agent that treats a cardiovascular disorder. In
some embodiments, administration of the second active agent partially or
fully results in undesired inflammation. In some embodiments, the second
active agent is niacin; a fibrate; a statin; an apolipoprotein A-1
modulator; an ACAT modulator; a CETP modulator; a glycoprotein IIb/IIIa
modulator; a P2Y12 modulator; an Lp-PLA2 modulator; an anti-hypertensive;
a leukotriene inhibitor; an 5-LO inhibitor; a FLAP inhibitor; or
combinations thereof. In some embodiments, the disorder is
hyperlipidemia; hypercholesterolemia; hyperglyceridemia; combined
hyperlipidemia; hypolipoproteinemia; hypocholesterolemia;
abetlipoproteinemia; Tangier disease; acute coronary syndrome; unstable
angina; non-ST segment elevation myocardial infarction; ST segment
elevation myocardial infarction; stable angina; Prinzmetal's angina;
arteriosclerosis; atherosclerosis; arteriolosclerosis; stenosis;
restenosis; venous thrombosis; arterial thrombosis; stroke; transient
ischemic attack; peripheral vascular disease; coronary artery disease;
hypertension; or combinations thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0024]Disclosed herein, in certain embodiments, are methods and
pharmaceutical compositions for modulating a disorder of a cardiovascular
system synergistic combination of (a) a therapeutically-effective amount
of a first active agent that inhibits inflammation and treats a
cardiovascular disorder selected from (1) a modulator of MIF; (2) a
modulator of an interaction between RANTES and Platelet Factor 4; or (3)
combinations thereof; and (b) a second active agent selected from an
agent that treats a cardiovascular disorder (the "cardiovascular disorder
agent").

[0025]In some embodiments, the combination is synergistic and results in a
more efficacious therapy. In some embodiments, the therapy
synergistically treats cardiovascular disorders by (a) targeting multiple
pathways that result in (either partially or fully) development of a
cardiovascular disorder (e.g., LDL concentrations and the chemotaxis of
macrophages) and (b) treating and/or ameliorating undesired inflammation
(e.g, myositis) resulting from the cardiovascular disorder agent. In some
embodiments, the therapy synergistically treats cardiovascular disorders
by targeting multiple pathways that result in (either partially or fully)
development of a cardiovascular disorder (e.g., LDL concentrations and
the chemotaxis of macrophages).

[0026]In some embodiments, the combination rescues a mammal from
inflammation partially or fully caused by the cardiovascular disorder
agent. In some embodiments, the combination allows (partially or fully) a
medical professional to increase the prescribed dosage of the
cardiovascular disorder agent. In some embodiments, the combination
enables (partially or fully) a medical professional to prescribe the
cardiovascular disorder agent (i.e., co-administration rescues the
cardiovascular disorder agent).

[0027]In some embodiments, the first active agent (i.e., a MIF antagonist
and/or a modulator of an interaction between RANTES and Platelet Factor
4), and a statin synergistically treat a CVD by (1) decreasing the
chemotaxis of leukocytes, and (2) decreasing (either partially or fully)
cholesterol synthesis. In some embodiments, first active agent further
treats undesired inflammation resulting from administration of the
statin.

[0028]In some embodiments, the first active agent (i.e., a MIF antagonist
and/or a modulator of an interaction between RANTES and Platelet Factor
4) and a fibrate synergistically treat a CVD by (1) decreasing the
chemotaxis of leukocytes, and (2) increasing the concentration of HDL. In
some embodiments, the first active agent also decreases any undesired
inflammation resulting from administration of the fibrate.

[0029]In some embodiments, the first active agent (i.e., a MIF antagonist
and/or a modulator of an interaction between RANTES and Platelet Factor
4) and a ApoA1 modulator synergistically treat a CVD by (1) decreasing
the chemotaxis of leukocytes, and (2) increasing the concentration of
HDL. In some embodiments, the first active agent also decreases any
undesired inflammation resulting from administration of the ApoA1
modulator.

[0030]In some embodiments, the first active agent (i.e., a MIF antagonist
and/or a modulator of an interaction between RANTES and Platelet Factor
4) and a ACAT modulator synergistically treat a CVD by (1) decreasing the
chemotaxis of leukocytes, and (2) decreasing (a) the production and
release of apoB-containing lipoproteins and (b) foam cell formation. In
some embodiments, the first active agent also decreases any undesired
inflammation resulting from administration of the ACAT inhibitor.

[0031]In some embodiments, the first active agent (i.e., a MIF antagonist
and/or a modulator of an interaction between RANTES and Platelet Factor
4) and a CETP modulator synergistically treat a CVD by (1) decreasing the
chemotaxis of leukocytes, and (2) decreasing the transfer cholesterol
from HDL cholesterol to LDL. In some embodiments, the first active agent
also decreases any undesired inflammation resulting from administration
of the CETP inhibitor.

[0032]In some embodiments, the first active agent (i.e., a MIF antagonist
and/or a modulator of an interaction between RANTES and Platelet Factor
4) and a GP IIb/IIIa receptor antagonist synergistically treat a CVD by
(1) decreasing the chemotaxis of leukocytes, and (2) inhibiting platelet
aggregation. In some embodiments, the first active agent also decreases
any undesired inflammation resulting from administration of the GP
IIb/IIIa receptor antagonist.

[0033]In some embodiments, the first active agent (i.e., a MIF antagonist
and/or a modulator of an interaction between RANTES and Platelet Factor
4) and a P2Y12 receptor antagonist synergistically treat a CVD by (1)
decreasing the chemotaxis of leukocytes, and (2) inhibiting platelet
aggregation. In some embodiments, the first active agent also decreases
any undesired inflammation resulting from administration of the P2Y12
receptor antagonist.

[0034]In some embodiments, the first active agent (i.e., a MIF antagonist
and/or a modulator of an interaction between RANTES and Platelet Factor
4) and a Lp-PLA2 antagonist synergistically treat a CVD by (1) decreasing
the chemotaxis of leukocytes, and (2) inhibiting the formation of
biologically active products from oxidized LDL. In some embodiments, the
first active agent also decreases any undesired inflammation resulting
from administration of the Lp-PLA2 antagonist.

CERTAIN DEFINITIONS

[0035]The terms "individual," "individual," or "subject" are used
interchangeably. As used herein, they mean any mammal (i.e. species of
any orders, families, and genus within the taxonomic classification
animalia: chordata: vertebrata: mammalia). In some embodiments, the
mammal is a human. In some embodiments, the mammal is a non-human. In
some embodiments, the mammal is a member of the taxonomic orders:
primates (e.g. lemurs, lorids, galagos, tarsiers, monkeys, apes, and
humans); rodentia (e.g. mice, rats, squirrels, chipmunks, and gophers);
lagomorpha (e.g. hares, rabbits, and pika); erinaceomorpha (e.g.
hedgehogs and gymnures); soricomorpha (e.g. shrews, moles, and
solenodons); chiroptera (e.g., bats); cetacea (e.g. whales, dolphins, and
porpoises); carnivora (e.g. cats, lions, and other feliformia; dogs,
bears, weasels, and seals); perissodactyla (e.g. horse, zebra, tapir, and
rhinoceros); artiodactyla (e.g. pigs, camels, cattle, and deer);
proboscidea (e.g. elephants); sirenia (e.g. manatees, dugong, and sea
cows); cingulata (e.g. armadillos); pilosa (e.g. anteaters and sloths);
didelphimorphia (e.g. american opossums); paucituberculata (e.g. shrew
opossums); microbiotheria (e.g. Monito del Monte); notoryctemorphia (e.g.
marsupial moles); dasyuromorphia (e.g. marsupial carnivores);
peramelemorphia (e.g. bandicoots and bilbies); or diprotodontia (e.g.
wombats, koalas, possums, gliders, kangaroos, wallaroos, and wallabies).
In some embodiments, the animal is a reptile (i.e. species of any orders,
families, and genus within the taxonomic classification animalia:
chordata: vertebrata: reptilia). In some embodiments, the animal is a
bird (i.e. animalia: chordata: vertebrata: ayes). None of the terms
require or are limited to situation characterized by the supervision
(e.g. constant or intermittent) of a health care worker (e.g. a doctor, a
registered nurse, a nurse practitioner, a physician's assistant, an
orderly, or a hospice worker).

[0036]The terms "treat," "treating" or "treatment," and other grammatical
equivalents as used herein, include alleviating, inhibiting or reducing
symptoms, reducing or inhibiting severity of, reducing incidence of,
prophylactic treatment of, reducing or inhibiting recurrence of,
preventing, delaying onset of, delaying recurrence of, abating or
ameliorating a disease or condition symptoms, ameliorating the underlying
metabolic causes of symptoms, inhibiting the disease or condition, e.g.,
arresting the development of the disease or condition, relieving the
disease or condition, causing regression of the disease or condition,
relieving a condition caused by the disease or condition, or stopping the
symptoms of the disease or condition. The terms further include achieving
a therapeutic benefit. By therapeutic benefit is meant eradication or
amelioration of the underlying disorder being treated, and/or the
eradication or amelioration of one or more of the physiological symptoms
associated with the underlying disorder such that an improvement is
observed in the individual.

[0037]The terms "prevent," "preventing" or "prevention," and other
grammatical equivalents as used herein, include preventing additional
symptoms, preventing the underlying metabolic causes of symptoms,
inhibiting the disease or condition, e.g., arresting the development of
the disease or condition and are intended to include prophylaxis. The
terms further include achieving a prophylactic benefit. For prophylactic
benefit, the compositions are optionally administered to an individual at
risk of developing a particular disease, to an individual reporting one
or more of the physiological symptoms of a disease, or to an individual
at risk of reoccurrence of the disease.

[0038]Where combination treatments or prevention methods are contemplated,
it is not intended that the agents described herein be limited by the
particular nature of the combination. For example, the agents described
herein are optionally administered in combination as simple mixtures as
well as chemical hybrids. An example of the latter is where the agent is
covalently linked to a targeting carrier or to an active pharmaceutical.
Covalent binding can be accomplished in many ways, such as, though not
limited to, the use of a commercially available cross-linking agent.
Furthermore, combination treatments are optionally administered
separately or concomitantly.

[0039]As used herein, the terms "pharmaceutical combination",
"administering an additional therapy", "administering an additional
therapeutic agent" and the like refer to a pharmaceutical therapy
resulting from the mixing or combining of more than one active ingredient
and includes both fixed and non-fixed combinations of the active
ingredients. The term "fixed combination" means that at least one of the
agents described herein, and at least one co-agent, are both administered
to an individual simultaneously in the form of a single entity or dosage.
The term "non-fixed combination" means that at least one of the agents
described herein, and at least one co-agent, are administered to an
individual as separate entities either simultaneously, concurrently or
sequentially with variable intervening time limits, wherein such
administration provides effective levels of the two or more agents in the
body of the individual. In some instances, the co-agent is administered
once or for a period of time, after which the agent is administered once
or over a period of time. In other instances, the co-agent is
administered for a period of time, after which, a therapy involving the
administration of both the co-agent and the agent are administered. In
still other embodiments, the agent is administered once or over a period
of time, after which, the co-agent is administered once or over a period
of time. These also apply to cocktail therapies, e.g. the administration
of three or more active ingredients.

[0040]As used herein, the terms "co-administration", "administered in
combination with" and their grammatical equivalents are meant to
encompass administration of the selected therapeutic agents to a single
individual, and are intended to include treatment regimens in which the
agents are administered by the same or different route of administration
or at the same or different times. In some embodiments the agents
described herein will be co-administered with other agents. These terms
encompass administration of two or more agents to an animal so that both
agents and/or their metabolites are present in the animal at the same
time. They include simultaneous administration in separate compositions,
administration at different times in separate compositions, and/or
administration in a composition in which both agents are present. Thus,
in some embodiments, the agents described herein and the other agent(s)
are administered in a single composition. In some embodiments, the agents
described herein and the other agent(s) are admixed in the composition.

[0041]The terms "effective amount" or "therapeutically effective amount"
as used herein, refer to a sufficient amount of at least one agent being
administered which achieve a desired result, e.g., to relieve to some
extent one or more symptoms of a disease or condition being treated. In
certain instances, the result is a reduction and/or alleviation of the
signs, symptoms, or causes of a disease, or any other desired alteration
of a biological system. In specific instances, the result is a decrease
in the growth of, the killing of, or the inducing of apoptosis in at
least one abnormally proliferating cell, e.g., a cancer stem cell. In
certain instances, an "effective amount" for therapeutic uses is the
amount of the composition comprising an agent as set forth herein
required to provide a clinically significant decrease in a disease. An
appropriate "effective" amount in any individual case is determined using
any suitable technique, such as a dose escalation study.

[0042]The terms "administer," "administering", "administration," and the
like, as used herein, refer to the methods that may be used to enable
delivery of agents or compositions to the desired site of biological
action. These methods include, but are not limited to oral routes,
intraduodenal routes, parenteral injection (including intravenous,
subcutaneous, intraperitoneal, intramuscular, intravascular or infusion),
topical and rectal administration. Administration techniques that are
optionally employed with the agents and methods described herein, include
e.g., as discussed in Goodman and Gilman, The Pharmacological Basis of
Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical
Sciences (current edition), Mack Publishing Co., Easton, Pa. In certain
embodiments, the agents and compositions described herein are
administered orally.

[0043]The term "pharmaceutically acceptable" as used herein, refers to a
material that does not abrogate the biological activity or properties of
the agents described herein, and is relatively nontoxic (i.e., the
toxicity of the material significantly outweighs the benefit of the
material). In some instances, a pharmaceutically acceptable material may
be administered to an individual without causing significant undesirable
biological effects or significantly interacting in a deleterious manner
with any of the components of the composition in which it is contained.

[0044]The term "carrier" as used herein, refers to relatively nontoxic
chemical agents that, in certain instances, facilitate the incorporation
of an agent into cells or tissues.

[0045]"Pharmaceutically acceptable prodrug" as used herein, refers to any
pharmaceutically acceptable salt, ester, salt of an ester or other
derivative of an agent, which, upon administration to a recipient, is
capable of providing, either directly or indirectly, a agent of this
invention or a pharmaceutically active metabolite or residue thereof.
Particularly favored prodrugs are those that increase the bioavailability
of the agents of this invention when such agents are administered to an
individual (e.g., by allowing an orally administered agent to be more
readily absorbed into blood) or which enhance delivery of the parent
agent to a biological compartment (e.g., the brain or lymphatic system).
In various embodiments, pharmaceutically acceptable salts described
herein include, by way of non-limiting example, a nitrate, chloride,
bromide, phosphate, sulfate, acetate, hexafluorophosphate, citrate,
gluconate, benzoate, propionate, butyrate, sulfosalicylate, maleate,
laurate, malate, fumarate, succinate, tartrate, amsonate, pamoate,
p-toluenenesulfonate, mesylate and the like. Furthermore,
pharmaceutically acceptable salts include, by way of non-limiting
example, alkaline earth metal salts (e.g., calcium or magnesium), alkali
metal salts (e.g., sodium or potassium), ammonium salts and the like.

[0046]The term "recruiting of monocytes" as described herein includes the
migration of monocytes into or out of the endothelium, their attachment
and propagation, for example, into endothelial fissures. The attachment
of monocytes is also known as monocyte adhesion, or as monocyte arrest
when the attachment occurs in shear flow as under physiological
conditions, for example, in blood capillaries, microvascular or arterial
streamlines.

[0047]By the term "polypeptide" is meant synthetic or nonsynthetic peptide
compounds, as well as purified, modified fragments of natural proteins,
native forms or recombinant peptides or proteins. The term "polypeptide"
likewise includes pharmacologically acceptable salts, pharmacologically
acceptable derivatives and/or conjugates of the corresponding
polypeptide.

[0049]The term "peptide mimetic", "mimetic peptide" and "analog" are used
herein interchangeably for the purposes of the specifications and claims,
to mean a peptide that mimics part or all of the bioactivity of an
endogenous protein ligand. In one embodiment, peptide mimetics are
modeled after a specific peptide and display an altered peptide backbone,
altered amino acids and/or an altered primary amino acid sequence when
compared to the peptide of which is was designed to mimic.

[0050]As used herein, the terms "antibody" and "antibodies" refer to
monoclonal antibodies, polyclonal antibodies, bi-specific antibodies,
multispecific antibodies, grafted antibodies, human antibodies, humanized
antibodies, synthetic antibodies, chimeric antibodies, camelized
antibodies, single-chain Fvs (scFv), single chain antibodies, Fab
fragments, F(ab') fragments, disulfide-linked Fvs (sdFv), intrabodies,
and anti-idiotypic (anti-Id) antibodies and antigen-binding fragments of
any of the above. In particular, antibodies include immunoglobulin
molecules and immunologically active fragments of immunoglobulin
molecules, i.e., molecules that contain an antigen binding site.
Immunoglobulin molecules are of any type (e.g., IgG, IgE, IgM, IgD, IgA
and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4,
IgA1 and IgA2) or subclass. The terms "antibody" and
immunoglobulin are used interchangeably in the broadest sense. In some
embodiments an antibody is part of a larger fusion molecule, formed by
covalent or non-covalent association of the antibody with one or more
other proteins or peptides.

[0051]As used herein, the term "derivative" in the context of a
polypeptide or protein, e.g. an antibody, refers to a polypeptide or
protein that comprises an amino acid sequence which has been altered by
the introduction of amino acid residue substitutions, deletions or
additions. The term "derivative" as used herein also refers to a
polypeptide or protein which has been modified, i.e., by the covalent
attachment of any type of molecule to the antibody. For example, in some
embodiments a polypeptide or protein is modified, e.g., by glycosylation,
acetylation, pegylation, phosphorylation, amidation, derivatization by
protecting/blocking groups, proteolytic cleavage, linkage to a cellular
ligand or other protein, etc. In some embodiments, derivatives,
polypeptides or proteins are produced by chemical modifications using
techniques, including, but not limited to specific chemical cleavage,
acetylation, formylation, metabolic synthesis of tunicamycin, etc. In
some embodiments a derivative a polypeptide or protein possesses a
similar or identical function as the polypeptide or protein from which it
was derived.

[0052]The terms "full length antibody", "intact antibody" and "whole
antibody" are used herein interchangeably, to refer to an antibody in its
substantially intact form, and not antibody fragments as defined below.
These terms particularly refer to an antibody with heavy chains contains
Fc regions. In some embodiments an antibody variant of the invention is a
full length antibody. In some embodiments the full length antibody is
human, humanized, chimeric, and/or affinity matured.

[0053]An "affinity matured" antibody is one having one or more alteration
in one or more CDRs thereof which result in an improvement in the
affinity of the antibody for antigen, compared to a parent antibody which
does not possess those alteration(s). Preferred affinity matured
antibodies will have nanomolar or even picomolar affinities for the
target antigen. Affinity matured antibodies are produced by procedures,
such as for example, Marks et al., (1992) Biotechnology 10:779-783 that
describes affinity maturation by variable heavy chain (VH) and variable
light chain (VL) domain shuffling. Random mutagenesis of CDR and/or
framework residues is described in: Barbas, et al. (1994) Proc. Nat.
Acad. Sci, USA 91:3809-3813; Shier et al., (1995) Gene 169:147-155;
Yelton et al., 1995, J. Immunol. 155:1994-2004; Jackson et al., 1995, J.
Immunol. 154(7):3310-9; and Hawkins et al, (19920, J. Mol. Biol.
226:889-896, for example.

[0055]"Fab" fragments are typically produced by papain digestion of
antibodies resulting in the production of two identical antigen-binding
fragments, each with a single antigen-binding site and a residual "Fc"
fragment. Pepsin treatment yields a F(ab')2 fragment that has two
antigen-combining sites capable of cross-linking antigen. An "Fv" is the
minimum antibody fragment that contains a complete antigen recognition
and binding site. In a two-chain Fv species, this region consists of a
dimer of one heavy- and one light-chain variable domain in tight,
non-covalent association. In a single-chain Fv (scFv) species, one heavy-
and one light-chain variable domain are covalently linked by a flexible
peptide linker such that the light and heavy chains associate in a
"dimeric" structure analogous to that in a two-chain Fv species. It is in
this configuration that the three CDRs of each variable domain interact
to define an antigen-binding site on the surface of the VH-VL dimer.
Collectively, the six CDRs confer antigen-binding specificity to the
antibody. However, even a single variable domain (or half of an Fv
comprising only three CDRs specific for an antigen) has the ability to
recognize and bind antigen, although usually at a lower affinity than the
entire binding site.

[0056]The Fab fragment also contains the constant domain of the light
chain and the first constant domain (CH1) of the heavy chain. Fab
fragments differ from Fab' fragments by the addition of a few residues at
the carboxy terminus of the heavy-chain CH1 domain including one or
more cysteines from the antibody hinge region. Fab'-SH is the designation
herein for Fab' in which the cysteine residue(s) of the constant domains
bear a free thiol group. F(ab')2 antibody fragments originally were
produced as pairs of Fab' fragments that have hinge cysteines between
them. Methods for producing the various fragments from monoclonal Abs
include, e.g., Pluckthun, 1992, Immunol. Rev. 130:152-188.

[0057]The term "monoclonal antibody" as used herein refers to an antibody
obtained from a population of substantially homogeneous antibodies, i.e.,
the individual antibodies comprising the population are identical except
for possible naturally occurring mutations that are present in minor
amounts. In some embodiments monoclonal antibodies are made, for example,
by the hybridoma method first described by Kohler and Milstein (1975)
Nature 256:495, or are made by recombinant methods, e.g., as described in
U.S. Pat. No. 4,816,567. In some embodiments monoclonal antibodies are
isolated from phage antibody libraries using the techniques described in
Clackson et al., Nature 352:624-628 (1991), as well as in Marks et al.,
J. Mol. Biol. 222:581-597 (1991).

[0058]As used herein, the term "epitope" refers to a fragment of a
polypeptide or protein having antigenic or immunogenic activity in an
animal, preferably in a mammal, and most preferably in a human. An
epitope having immunogenic activity is a fragment of a polypeptide or
protein that elicits an antibody response in an animal. An epitope having
antigenic activity is a fragment of a polypeptide or protein to which an
antibody immunospecifically binds as determined by any method, for
example by immunoassays. Antigenic epitopes need not necessarily be
immunogenic.

[0059]The phrase "specifically binds" when referring to the interaction
between an antibody or other binding molecule and a protein or
polypeptide or epitope, typically refers to an antibody or other binding
molecule that recognizes and detectably binds with high affinity to the
target of interest. Preferably, under designated or physiological
conditions, the specified antibodies or binding molecules bind to a
particular polypeptide, protein or epitope yet does not bind in a
significant or undesirable amount to other molecules present in a sample.
In other words the specified antibody or binding molecule does not
undesirably cross-react with non-target antigens and/or epitopes.
Further, in some embodiments, an antibody that specifically binds, binds
through the variable domain or the constant domain of the antibody. For
the antibody that specifically binds through its variable domain, it is
not aggregated, i.e., is monomeric. A variety of immunoassay formats are
used to select antibodies or other binding molecule that are
immunoreactive with a particular polypeptide and have a desired
specificity. For example, solid-phase ELISA immunoassays, BIAcore, flow
cytometry and radioimmunoassays are used to select monoclonal antibodies
having a desired immunoreactivity and specificity. See, Harlow, 1988,
ANTIBODIES, A LABORATORY MANUAL, Cold Spring Harbor Publications, New
York (hereinafter, "Harlow"), for a description of immunoassay formats
and conditions that are used to determine or assess immunoreactivity and
specificity. "Selective binding", "selectivity", and the like refer the
preference of a antibody to interact with one molecule as compared to
another. Preferably, interactions between antibodies, particularly
modulators, and proteins are both specific and selective. Note that in
some embodiments a small antibody is designed to "specifically bind" and
"selectively bind" two distinct, yet similar targets without binding to
other undesirable targets.

RANTES and Platelet Factor 4 (PF4)

[0060]In some embodiments, the methods and compositions disclosed herein
inhibit (partially or fully) the activity of RANTES. RANTES (also known
as CCL5) is a pro-inflammatory chemokine In certain instances, it is
secreted by an activated platelet in response to an inflammation or
tissue injury. In certain instances, RANTES is a ligand for a CCR5
receptor found on the plasma membrane of a target leukocyte (e.g.
monocyte). In certain instances, RANTES induces chemotaxis in nearby
leukocytes (e.g. monocytes) along a RANTES gradient. In certain
instances, RANTES induces the chemotaxis of a leukocyte to the site of an
inflammation or tissue injury. In certain instances, the chemotaxis of
monocytes along a RANTES gradient results in monocyte arrest (i.e., the
deposition of monocytes on epithelium) at the site of injury or
inflammation.

[0061]In some embodiments, the methods and compositions disclosed herein
inhibit (partially or fully) the activity of Platelet Factor 4 (PF4). PF4
(also known as CXCL4) is a chemokine In certain instances, it is secreted
by the alpha granules of an activated platelet during platelet
aggregation in response to tissue injury and/or inflammation. In certain
instances, PF4 is a ligand for a CXC3 receptor (i.e., CXC3RB). In certain
instances, it induces directed chemotaxis in nearby leukocytes (e.g.
monocytes). In certain instances, PF4 induces the chemotaxis of a
leukocyte to the site of an inflammation or tissue injury.

[0062]In certain instances, RANTES and PF4 form a heteromultimer (e.g., a
heterodimer). In certain instances, a RANTES and PF4 heteromultimer
(e.g., a heterodimer) amplifies the effects of RANTES-induced monocyte
arrest. In certain instances, inhibiting the formation of a RANTES/PF4
heteromultimer (e.g., a heterodimer) decreases monocyte arrest.

Inflammatory Disorders

[0063]In some embodiments, the methods and compositions described herein
treat inflammation (e.g., acute or chronic). In certain instances,
inflammation results from (either partially or fully) an infection. In
certain instances, inflammation results from (either partially or fully)
damage to a tissue (e.g., by a burn, by frostbite, by exposure to a
cytotoxic agent, or by trauma). In certain instances, inflammation
results from (either partially or fully) an autoimmune disorder. In
certain instances, inflammation results from (either partially or fully)
the presence of a foreign body (e.g., a splinter). In certain instances,
inflammation results from exposure to a toxin and/or chemical irritant.

[0064]As used herein, "acute inflammation" refers to inflammation
characterized in that it develops over the course of a few minutes to a
few hours, and ceases once the stimulus has been removed (e.g., an
infectious agent has been killed by an immune response or administration
of a therapeutic agent, a foreign body has been removed by an immune
response or extraction, or damaged tissue has healed). The short duration
of acute inflammation results from the short half-lives of most
inflammatory mediators.

[0065]In certain instances, acute inflammation begins with the activation
of leukocytes (e.g., monocytes, macrophages, neutrophils, basophils,
eosinophils, lymphocytes, dendritic cells, and mastocytes). In certain
instances, the leukocytes release inflammatory mediators (e.g.,
histamines, proteoglycans, serine proteases, eicosanoids, and cytokines).
In certain instances, inflammatory mediators result in (either partially
or fully) the symptoms associated with inflammation. For example, in
certain instances an inflammatory mediator dilates post capillary
venules, and increases blood vessel permeability. In certain instances,
the increased blood flow that follows vasodilation results in (either
partially or fully) rubor and calor. In certain instances, increased
permeability of the blood vessels results in an exudation of plasma into
the tissue leading to edema. In certain instances, the latter allows
leukocytes to migrate along a chemotactic gradient to the site of the
inflammatory stimulant. Further, in certain instances, structural changes
to blood vessels (e.g., capillaries and venules) occur. In certain
instances, the structural changes are induced (either partially or fully)
by monocytes and/or macrophages. In certain instances, the structural
changes include, but are not limited to, remodeling of vessels, and
angiogenesis. In certain instances, angiogenesis contributes to the
maintenance of chronic inflammation by allowing for increased transport
of leukocytes. Additionally, in certain instances, histamines and
bradykinin irritate nerve endings leading to itching and/or pain.

[0066]In certain instances, chronic inflammation results from the presence
of a persistent stimulant (e.g., persistent acute inflammation, bacterial
infection (e.g., by Mycobacterium tuberculosis), prolonged exposure to
chemical agents (e.g., silica, or tobacco smoke) and autoimmune reactions
(e.g., rheumatoid arthritis)). In certain instances, the persistent
stimulant results in continuous inflammation (e.g., due to the continuous
recruitment of monocytes, and the proliferation of macrophages). In
certain instances, the continuous inflammation further damages tissues
which results in the additional recruitment of mononuclear cells thus
maintaining and exacerbating the inflammation. In certain instances,
physiological responses to inflammation further include angiogenesis and
fibrosis.

[0072]As used herein, "allergy" means a disorder characterized by
excessive activation of mast cells and basophils by IgE. In certain
instances, the excessive activation of mast cells and basophils by IgE
results (either partially or fully) in an inflammatory response. In
certain instances, the inflammatory response is local. In certain
instances, the inflammatory response results in the narrowing of airways
(i.e., bronchoconstriction). In certain instances, the inflammatory
response results in inflammation of the nose (i.e., rhinitis). In certain
instances, the inflammatory response is systemic (i.e., anaphylaxis).

[0073]In some embodiments, the methods and compositions described herein
treat angiogenesis. As used herein, "angiogenesis" refers to the
formations of new blood vessels. In certain instances, angiogenesis
occurs with chronic inflammation. In certain instances, angiogenesis is
induced by monocytes and/or macrophages.

[0075]In some embodiments, the methods and compositions described herein
treat obesity. As used herein, "obesity" means an accumulation of adipose
tissue with a BMI of greater than or equal to 30 kg/m2. In certain
instances, obesity is characterized a proinflammatory state, increasing
the risk of thrombosis. In certain instances, obesity is associated with
a low-grade inflammation of white adipose tissue (WAT). In certain
instances, WAT associated with obesity is characterized by an increased
production and secretion of a wide range of inflammatory molecules
including TNF-alpha and interleukin-6 (IL-6). In certain instances, WAT
is infiltrated by macrophages, which produce pro-inflammatory cytokines.
In certain instances, TNF-alpha is overproduced in adipose tissue. In
certain instances, IL-6 production increases during obesity.

[0077]The terms "anti-inflammatory agent" and "modulator of inflammation"
are used interchangeably. As used herein, the terms refer to agents treat
inflammation and/or an inflammatory disorder. In some embodiments, the
anti-inflammatory agent is an anti-TNF agent, an IL-1 receptor
antagonist, an IL-2 receptor antagonist, a cytotoxic agent, an
immunomodulatory agent, an antibiotic, a T-cell co-stimulatory blocker, a
B cell depleting agent, an immunosuppressive agent (e.g., cyclosporine
A), an alkylating agent, an anti-metabolite, a plant alkaloid, a
terpenoids, a topoisomerase inhibitor, an antitumour antibiotic, an
antibody, a hormonal therapy (e.g., aromatase inhibitors), a leukotriene
inhibitor, or combinations thereof.

[0080]In some embodiments, the methods and compositions described herein
treat dyslipidemia. As used herein, the term "dyslipidemia" means a
disruption (i.e., variation from a normal range) in the concentration of
a lipid in the blood.

[0083]HDL is a type of lipoprotein that transports cholesterol and
triglycerides to the liver. In certain instances, HDL comprises ApoA1 and
ApoA2. In certain instances, ApoA1 and ApoA2 are expressed in the liver.
In certain instances, the liver synthesized HDL.

[0084]In certain instances, HDL transport cholesterol from cells to the
liver, adrenals, ovary and/or testes. In certain instances, cholesterol
transported to the liver is excreted as bile. In certain instances,
cholesterol transported to adrenals, ovaries and/or testes are used to
synthesize steroid hormones.

[0086]In certain instances, increasing the concentration of HDL across all
or most sub-classes results in the production of reactive oxygen species
(ROS). In certain instances, an enzyme associated with HDL modifies a
phospholipid into an oxidized phospholipid. In certain instances, an
enzyme associated with HDL modifies cholesterol into an oxidized sterol.
In certain instances, an oxidized sterol and/or an oxidized phospholipid
results in pro-inflammatory and/or pro-atherogenic HDL.

[0087]In certain instances, cholesteryl ester transfer protein (CETP)
exchanges triglycerides transported by VLDL (very low density
lipoprotein) for cholesteryl esters transported by HDL. In certain
instances, the exchange of triglycerides for cholesteryl esters results
in VLDL being processed into LDL. In certain instances, LDL is removed
from circulation by the LDL receptor pathway. In certain instances, the
triglycerides are degraded by hepatic lipase. In certain instances,
delipidified HDL recirculate in the blood and transport additional lipids
to the liver.

[0089]Low-density lipoprotein (LDL) is a type of lipoprotein that
transports cholesterol and triglycerides from the liver to peripheral
tissues. In certain instances, LDL comprises an apolipoprotein B (ApoB).
In certain instances, ApoB is expressed as two isoforms, ApoB48 and
ApoB100. In certain instances, ApoB48 is synthesized by intestinal cells.
In certain instances, ApoB100 is synthesized in the liver. In certain
instances, Hsp110 stabilizes of ApoB.

Cardiovascular Disorders

[0090]In some embodiments, the methods and compositions described herein
treat atherosclerosis. As used herein, "atherosclerosis" means
inflammation of an arterial wall. In certain instance, the inflammation
results from (partially or fully) the accumulation of macrophage white
blood cells. In certain instances, the inflammation results from
(partially or fully) the presence of oxidized LDL. In certain instances,
oxidized LDL damages an arterial wall. In certain instances, monocytes
respond to (i.e., follow a chemotactic gradient to) the damaged arterial
wall. In certain instances, the monocytes differentiate into macrophages.
In certain instances, macrophages endocytose the oxidized-LDL (cells such
as macrophages with endocytosed LDL are called "foam cells"). In certain
instances, a foam cell dies. In certain instances, the rupture of a foam
cell deposits oxidized cholesterol into the artery wall. In certain
instances, the arterial wall becomes inflamed due to the damaged caused
by the oxidized LDL. In certain instances, cells form a hard covering
over the inflamed area. In certain instances, the cellular covering
narrows an artery.

[0091]In certain instances, an atheromatous plaque is divided into three
distinct components: (a) the atheroma (i.e., a nodular accumulation of a
soft, flaky, yellowish material comprised of macrophages nearest the
lumen of the artery; (b) areas of cholesterol crystals; and (c)
calcification at the outer base.

[0092]In certain instances, an atherosclerotic plaque results (partially
or fully) in stenosis (i.e., the narrowing of blood vessel). In certain
instances, stenosis results (partially or fully) in decreased blood flow.
In some embodiments, the methods and compositions described herein treat
stenosis and/or restenosis. In certain instances, an atherosclerotic
plaque results (partially or fully) in the development of an aneurysm. In
some embodiments, the methods and compositions described herein treat an
aneurysm. In certain instances, the rupture of an atherosclerotic plaque
results (partially or fully) in an infarction (i.e., the deprivation of
oxygen) to a tissue. In some embodiments, the methods and compositions
described herein treat an infarction.

[0093]In some embodiments, the methods and compositions described herein
treat a myocardial infarction. "Myocardial infarction" and "heart attack"
are used interchangeably. As used herein, both terms refer to an
interruption in the blood supply to the heart. In certain instances, an
interruption in the blood supply to the heart results from (partially or
fully) the occlusion of a coronary artery by a ruptured atherosclerotic
plaque. In certain instances, occlusion of an artery results in the
infarction of myocardium. In certain instances, the infarction of
myocardium results in the scarring of myocardial tissue. In certain
instances, scarred of myocardial tissue conducts electrical impulses more
slowly than unscarred tissue. In certain instances, the difference in
conduction velocity between scarred and unscarred tissue results
(partially or fully) in ventricular fibrillation or ventricular
tachycardia.

[0094]In some embodiments, the methods and compositions described herein
treat an angina (e.g., stable or unstable). As used herein, "angina
pectoris" refers chest pain resulting from (partially or fully) of the
heart.

[0095]In some embodiments, the methods and compositions described herein
treat a thrombosis (venous or arterial). As used herein, "thrombosis"
refers to the formation of a blood clot. In certain instances, the blood
clot forms in a vein (i.e., venous thrombosis). In certain instances, the
blood clot forms in an artery (i.e., arterial thrombosis). In certain
instances, a piece of or the entire blood clot is transported (i.e., an
embolism) to the lungs (i.e., a pulmonary embolism). In some embodiments,
the methods and compositions described herein treat an embolism.

[0096]In some embodiments, the methods and compositions described herein
treat a stroke. As used herein, "stroke" refers to a loss of brain
function (e.g., necrosis of brain tissue) resulting from (partially or
fully) a disturbance in blood supply (e.g., ischemia). In certain
instances, a stroke results from (partially or fully) a thrombosis or an
embolism.

[0097]In certain instances, an atherosclerotic plaque results (partially
or fully) in the development of an aneurysm. In some embodiments, the
methods and compositions described herein treat an aneurysm. In some
embodiments, the methods and compositions described herein treat an
abdominal aortic aneurysm ("AAA"). As used herein, an "abdominal aortic
aneurysm" is a localized dilatation of the abdominal aorta. In certain
instances, the rupture of an AAA results in bleeding, leading to
hypovolemic shock with hypotension, tachycardia, cyanosis, and altered
mental status.

[0098]In some embodiments, the compositions and methods disclosed herein
treat abdominal aortic aneurysms. In certain instances, abdominal aortic
aneurysms result (partially or fully) from an extensive breakdown of
structural proteins (e.g., elastin and collagen). In some embodiments, a
method and/or composition disclosed herein partially or fully inhibits
the breakdown of a structural protein (e.g., elastin and collagen). In
certain instances, the breakdown of structural proteins is caused by
activated MMPs. In some embodiments, a method and/or composition
disclosed herein partially or fully inhibits the activation of an MMP. In
some embodiments, a composition and/or method disclosed herein inhibit
the upregulation of MMP-1, MMP-9 or MMP-12. In certain instances, MIF is
co-expressed with MMP-1, MMP-9, and MMP-12 in abdominal aortic aneurysms.
In certain instances, the MIF is upregulated in stable abdominal aortic
aneurysm and is intensified further in ruptured aneurysms. In certain
instances, MMPs are activated following infiltration of a section of the
abdominal aorta by leukocytes (e.g., macrophages and neutrophils). In
some embodiments, a method and/or composition disclosed herein partially
or fully inhibits the activity of MIF. In some embodiments, a method
and/or composition disclosed herein partially or fully inhibits the
infiltration of a section of the abdominal aorta by leukocytes.

Treatments for Cardiovascular Disorders

[0099]In some embodiments, the cardiovascular disorder is treated with an
active agent (the "cardiovascular disorder agent"). In some embodiments,
the active agent is niacin; a fibrate; a statin; an apolipoprotein A-1
modulator; an ACAT modulator; a CETP modulator; a glycoprotein IIb/IIIa
modulator; a P2Y12 modulator; an Lp-PLA2 modulator; or combinations
thereof.

[0100]In some embodiments, the cardiovascular disorder agent reduces the
risk of developing a cardiovascular disorder across all levels of HDL. In
some embodiments, the cardiovascular disorder agent inhibits (partially
or fully) the activity of 3-hydroxy-3-methylglutaryl coenzyme A
reductase. In some embodiments, the cardiovascular disorder agent is a
atorvastatin; cerivastatin; fluvastatin; lovastatin; mevastatin;
pitavastatin; pravastatin; rosuvastatin; simvastatin; simvastatin and
ezetimibe; lovastatin and niacin, extended-release; atorvastatin and
amlodipine besylate; simvastatin and niacin, extended-release; or
combinations thereof.

[0101]In some embodiments, the cardiovascular disorder agent raises HDL
non-selectively. In some embodiments, the cardiovascular disorder agent
down-regulates transcription of a CETP gene. In some embodiments, the
cardiovascular disorder agent is niacin.

[0102]In some embodiments, the cardiovascular disorder agent reduces the
risk of developing a cardiovascular disorder in individuals with low HDL
with metabolic syndrome. In some embodiments, the cardiovascular disorder
agent is bezafibrate; ciprofibrate; clofibrate; gemfibrozil; fenofibrate;
or combinations thereof.

[0103]In some embodiments, the cardiovascular disorder agent selectively
increases the levels of apoA1 protein (e.g. by transcriptional induction
of the gene encoding apoA1) and increases the production of nascent HDL
(apoA1-enriched). In some embodiments, the second active agent is DF4
(Ac-D-W--F--K-A-F--Y-D-K--V-A-E-K--F--K-E-A-F--NH2); DF5; RVX-208
(Resverlogix); or combinations thereof.

[0108]In some embodiments, the cardiovascular disorder agent inhibits
(partially or fully) the activity of lipoprotein-associated phospholipase
A2 (1p-PLA2). In some embodiments, the cardiovascular disorder agent
inhibits (partially of fully) the hydrolysis of the center (sn-2) ester
bond of phospholipids. In some embodiments, the cardiovascular disorder
agent inhibits (partially or fully) the production of oxidized fatty
acids and lysophosphatidyl choline. In some embodiments, the
cardiovascular disorder agent inhibits (partially or fully) the
chemotaxis of monocytes. In some embodiments, the cardiovascular disorder
agent is darapladib (SB 480848); SB-435-495 (GlaxoSmithKline); SB-222657
(GlaxoSmithKline); SB-253514 (GlaxoSmithKline); or combinations thereof.

[0110]In some embodiments, the cardiovascular disorder agent is
administered before, after, or simultaneously with the modulator of
inflammation.

[0111]In some embodiments, a cardiovascular disorder is treated by
delipidifying the blood of an individual. In some embodiments, the blood
of an individual is delipidified by removing a lipid from an HDL molecule
in an individual in need thereof. In some embodiments, administering a
therapeutically-effective amount of a modulator of inflammation acts in
synergy with the removal of a lipid from an HDL molecule.

Small Molecule Antagonists of RANTES and PF4

[0112]In some embodiments, the formation of a RANTES/PF4 heteromultimer
(e.g., a heterodimer) is disrupted by use of a small molecule that binds
to RANTES and/or a small molecule that binds to PF4. In some embodiments,
the small molecule antagonizes or inhibits (both partially or completely)
the interaction of PF4 and RANTES.

[0113]In some embodiments, the function of a RANTES/PF4 heteromultimer
(e.g., a heterodimer) is disrupted by use of a small molecule that binds
to a RANTES/PF4 heterodimer.

Antibody Antagonists of RANTES and PF4

[0114]In some embodiments, the formation of a RANTES/PF4 heteromultimer
(e.g., a heterodimer) is disrupted by use of an antibody that binds to
RANTES and/or an antibody that binds to PF4. In some embodiments, the
antibody antagonizes or inhibits (both partially or completely) the
interaction of PF4 and RANTES.

[0115]In some embodiments, the function of a RANTES/PF4 heteromultimer
(e.g., a heterodimer) is disrupted by use of an antibody that binds to a
RANTES/PF4 heterodimer.

[0116]The antibodies herein include monoclonal, polyclonal, recombinant,
chimeric, humanized, bi-specific, grafted, human, and fragments thereof
including antibodies altered by any means to be less immunogenic in
humans. Thus, for example, the monoclonal antibodies and fragments, etc.,
herein include "chimeric" antibodies and "humanized" antibodies. In
general, chimeric antibodies include a portion of the heavy and/or light
chain that is identical with or homologous to corresponding sequences in
antibodies derived from a particular species or belonging to a particular
antibody class or subclass, while the remainder of the chain(s) is
identical with or homologous to corresponding sequences in antibodies
derived from another species or belonging to another antibody class or
subclass, so long as they exhibit the desired biological activity. For
example in some embodiments a chimeric antibody contains variable regions
derived from a mouse and constant regions derived from human in which the
constant region contains sequences homologous to both human IgG2 and
human IgG4.

[0117]"Humanized" forms of non-human (e.g., murine) antibodies or
fragments are chimeric immunoglobulins, immunoglobulin chains or
fragments thereof (such as Fv, Fab, Fab', F(ab')2 or other
antigen-binding subsequences of antibodies) which contain minimal
sequence derived from non-human immunoglobulin. Humanized antibodies
include, grafted antibodies or CDR grafted antibodies wherein part or all
of the amino acid sequence of one or more complementarity determining
regions (CDRs) derived from a non-human animal antibody is grafted to an
appropriate position of a human antibody while maintaining the desired
binding specificity and/or affinity of the original non-human antibody.
In some embodiments, corresponding non-human residues replace Fv
framework residues of the human immunoglobulin. In some embodiments
humanized antibodies comprise residues that are found neither in the
recipient antibody nor in the imported CDR or framework sequences. These
modifications are made to further refine and optimize antibody
performance. In some embodiments, the humanized antibody comprises
substantially all of at least one, and typically two, variable domains,
in which all or substantially all of the CDR regions correspond to those
of a non-human immunoglobulin and all or substantially all of the FR
regions are those of a human immunoglobulin consensus sequence.

Peptide Antagonists of RANTES and PF4

[0118]In some embodiments, the interaction of RANTES and PF4 is disrupted
by use of a peptide antagonist that mimics all or part of RANTES. In some
embodiments, the interaction of RANTES and PF4 is disrupted by use of a
peptide antagonist that mimics the PF4 interacting domain of RANTES. In
certain instances, PF4 binds to the peptide antagonist and thus does not
bind to RANTES.

[0119]In some embodiments, the peptide antagonist is an isolated peptide,
pharmacologically acceptable salts, derivatives, and conjugates thereof.
In some embodiments, the peptide antagonist comprises a portion of a
RANTES amino acid sequence.

[0120]In some embodiments, the peptide antagonists described herein do not
effect (or only partially effect) the other functions of the RANTES
and/or PF4. In one embodiment, a selective blocking of the recruiting of
monocytes is achieved, for example, on endothelium.

[0121]In some embodiments, the peptide antagonists described herein
provide a high specificity, and do not effect (or only partially effect)
the many metabolic processes mediated by the chemokines RANTES and PF4,
for example, the immune or clotting systems.

[0122]In some embodiments, peptide antagonists comprises between 15 and 25
amino acids. In some embodiments, peptide antagonists comprise between 19
and 25 amino acids. In some embodiments, a peptide antagonist described
herein has a length of no more than 25 amino acids. In a further
embodiment, the peptide antagonist has a number of amino acids in the
range of about 15 to about 25 amino acids, and in a further embodiment,
in the range of about 15 to about 22 amino acids. In further embodiments,
the peptide antagonist has a number of amino acids in the range of about
18 to about 23 amino acids, including in the range of about 18 to about
22 amino acids, and including, in the range of about 19 to about 22 amino
acids, and also including in the range of about 20 to about 21 amino
acids. In certain embodiments, the peptide has 22 amino acids.

[0123]In one embodiment, the peptide antagonists described herein have a
cysteine residue at each of the amino-terminal and carboxy-terminal ends.
In some embodiments, the cysteine residue at the amino-terminus and the
cysteine residue at the carboxy terminus bind together, yielding a ring.
In one embodiment, a cyclical peptide antagonist has an improved
stability. In one embodiment, the peptide antagonists described herein
have a longer effectiveness and, accordingly, are used in smaller
amounts.

[0124]In some embodiments, the peptide antagonists described herein are
prepared by any suitable manner (e.g., literature methods).

wherein [0126]X1 is chosen from the group containing lysine, glutamine,
arginine, histidine and asparagine, or an amino acid deletion; [0127]X2
is chosen from the group containing glutamic acid, aspartic acid and
glutamine, or an amino acid deletion; [0128]X3 is chosen from the group
containing glycine, serine and alanine; [0129]X4 is chosen from the group
containing lysine, leucine and arginine; [0130]X5 is chosen from the
group containing serine, cysteine, glycine and threonine; [0131]X6 is
chosen from the group containing proline and alanine; [0132]X7 is chosen
from the group containing asparagine and glutamine; [0133]X8 is chosen
from the group containing proline, tyrosine and glycine; [0134]X9 is
chosen from the group containing glycine, alanine and serine; [0135]X10
is chosen from the group containing isoleucine, valine and asparagine;
[0136]X11 is chosen from the group containing valine, isoleucine and
asparagine; [0137]X12 is chosen from the group containing phenylalanine,
tyrosine, isoleucine, valine, leucine and methionine; [0138]X13 is chosen
from the group containing isoleucine, valine, leucine, methionine and
phenylalanine; [0139]X14 is chosen from the group containing threonine,
glycine, alanine, serine and tyrosine; [0140]X15 is chosen from the group
containing arginine, lysine, alanine, glutamine, histidine and
asparagine, or an amino acid deletion.

[0141]In some embodiments, the peptide antagonist is derived from a human
RANTES amino acid sequence. In certain instances, human RANTES is encoded
by a nucleotide sequence located on chromosome 17 at the cytogenic band
17q12 (per Ensemble cytogenic band) or 17q11.2-q12 (per Entrez Gene). In
some embodiments, the peptide antagonist comprises a portion of a human
RANTES amino acid sequence. In some embodiments, the peptide antagonist
has an amino acid sequence SEQ ID NO: 2, as indicated below:

TABLE-US-00016
C-KEYFYTSGKCSNPAVVFVTR-C.

[0142]In some embodiments, the peptide antagonist is derived from a mouse
RANTES amino acid sequence. In certain instances, mouse RANTES is encoded
by a nucleotide sequence located on chromosome 11 at the locus 11 (47.40
cM)4. In some embodiments, the peptide antagonist comprises a
portion of a mouse RANTES amino acid sequence. In some embodiments, the
peptide antagonist has an amino acid sequence SEQ ID NO: 3, as indicated
below:

TABLE-US-00017
C-KEYFYTSSKCSNLAVVFVTR-C.

[0143]In some embodiments, the peptide antagonist is derived from a pig
RANTES amino acid sequence. In some embodiments, the peptide antagonist
comprises a portion of a pig RANTES amino acid sequence. In some
embodiments, the peptide antagonist has an amino acid sequence SEQ ID NO:
4, as indicated below:

TABLE-US-00018
C-QEYFYTSSKCSMAAVVFITR-C.

[0144]In some embodiments, the peptide antagonist has an amino acid
sequence SEQ ID NO 5, as indicated below:

where: [0145]X1 is chosen from the group containing lysine, glutamine,
arginine, histidine and asparagine, or an amino acid deletion; [0146]X2
is chosen from the group containing glutamic acid, aspartic acid and
glutamine, or an amino acid deletion; [0147]X3 is chosen from the group
containing glycine, serine and alanine; [0148]X4 is chosen from the group
containing lysine, leucine and arginine; [0149]X5 is chosen from the
group containing serine, cysteine, glycine and threonine; [0150]X6 is
chosen from the group containing proline and alanine; [0151]X7 is chosen
from the group containing asparagine and glutamine; [0152]X8 is chosen
from the group containing proline, tyrosine and glycine; [0153]X9 is
chosen from the group containing glycine, alanine and serine; [0154]X10
is chosen from the group containing isoleucine, valine and asparagine;
[0155]X11 is chosen from the group containing valine, isoleucine and
asparagine; [0156]X12 is chosen from the group containing phenylalanine,
tyrosine, isoleucine, valine, leucine and methionine; [0157]X13 is chosen
from the group containing isoleucine, valine, leucine, methionine and
phenylalanine; [0158]X14 is chosen from the group containing threonine,
glycine, alanine, serine and tyrosine; and [0159]X15 is chosen from the
group containing arginine, lysine, alanine, glutamine, histidine and
asparagine, or an amino acid deletion.

where: [0161]X1 is chosen from the group containing lysine, glutamine,
arginine, histidine and asparagine, or an amino acid deletion; [0162]X2
is chosen from the group containing glutaminic acid, asparaginic acid and
glutamine, or an amino acid deletion; X3 is chosen from the group
containing glycine, serine and alanine; [0163]X4 is chosen from the group
containing lysine, leucine and arginine; [0164]X5 is chosen from the
group containing serine, cysteine, glycine and threonine; [0165]X6 is
chosen from the group containing serine, glycine and threonine; [0166]X7
is chosen from the group containing methionine, isoleucine, leucine, and
phenylalanine; [0167]X8 is chosen from the group containing proline,
tyrosine and glycine; [0168]X9 is chosen from the group containing
glycine, alanine and serine; [0169]X10 is chosen from the group
containing isoleucine, valine and asparagine; [0170]X11 is chosen from
the group containing valine, isoleucine and asparagine; [0171]X12 is
chosen from the group containing phenylalanine, tyrosine, isoleucine,
valine, leucine and methionine; [0172]X13 is chosen from the group
containing isoleucine, valine, leucine, methionine and phenylalanine;
[0173]X14 is chosen from the group containing threonine, glycine,
alanine, serine and tyrosine; and [0174]X15 is chosen from the group
containing arginine, alanine, lysine, glutamine, histidine and
asparagine, or an amino acid deletion.

where: [0176]X1 is chosen from the group containing lysine, glutamine,
arginine, histidine and asparagine, or an amino acid deletion; [0177]X2
is chosen from the group containing glutaminic acid, asparaginic acid and
glutamine, or an amino acid deletion; [0178]X3 is chosen from the group
containing glycine, serine and alanine; [0179]X4 is chosen from the group
containing lysine, leucine and arginine; [0180]X5 is chosen from the
group containing serine, cysteine, glycine and threonine; [0181]X6 is
chosen from the group containing serine, glycine and threonine; [0182]X7
is chosen from the group containing asparagine and glutamine; [0183]X8 is
chosen from the group containing leucine, isoleucine, phenylalanine,
alanine, valine, threonine and methionine; [0184]X9 is chosen from the
group containing glycine, alanine and serine; [0185]X10 is chosen from
the group containing isoleucine, valine and asparagine; [0186]X11 is
chosen from the group containing valine, isoleucine and asparagine;
[0187]X12 is chosen from the group containing phenylalanine, tyrosine,
isoleucine, valine, leucine and methionine; [0188]X13 is chosen from the
group containing isoleucine, valine, leucine, methionine and
phenylalanine; [0189]X14 is chosen from the group containing threonine,
glycine, alanine, serine and tyrosine; and [0190]X15 is chosen from the
group containing arginine, alanine, lysine, glutamine, histidine and
asparagine, or an amino acid deletion.

where: [0192]X1 is chosen from the group containing lysine, glutamine,
arginine, histidine and asparagine, or an amino acid deletion; [0193]X2
is chosen from the group containing glutaminic acid, asparaginic acid and
glutamine, or an amino acid deletion; [0194]X3 is chosen from the group
containing glycine, serine and alanine; [0195]X4 is chosen from the group
containing lysine, leucine and arginine; [0196]X5 is chosen from the
group containing serine, cysteine, glycine and threonine; [0197]X6 is
chosen from the group containing proline and alanine; [0198]X7 is chosen
from the group containing methionine, isoleucine, leucine, and
phenylalanine; [0199]X8 is chosen from the group containing proline,
tyrosine and glycine; [0200]X9 is chosen from the group containing
glycine, alanine and serine; [0201]X10 is chosen from the group
containing isoleucine, valine and asparagine; [0202]X11 is chosen from
the group containing valine, isoleucine and asparagine; [0203]X12 is
chosen from the group containing phenylalanine, tyrosine, isoleucine,
valine, leucine and methionine; [0204]X13 is chosen from the group
containing isoleucine, valine, leucine, methionine and phenylalanine;
[0205]X14 is chosen from the group containing threonine, glycine,
alanine, serine and tyrosine; and [0206]X15 is chosen from the group
containing arginine, alanine, lysine, glutamine, histidine and
asparagine, or an amino acid deletion.

where: [0208]X1 is chosen from the group containing lysine, glutamine,
arginine, histidine and asparagine, or an amino acid deletion; [0209]X2
is chosen from the group containing glutaminic acid, asparaginic acid and
glutamine, or an amino acid deletion; [0210]X3 is chosen from the group
containing glycine, serine and alanine; [0211]X4 is chosen from the group
containing lysine, leucine and arginine; [0212]X5 is chosen from the
group containing serine, cysteine, glycine and threonine; [0213]X6 is
chosen from the group containing serine, glycine and threonine; [0214]X7
is chosen from the group containing methionine, isoleucine, leucine, and
phenylalanine; [0215]X8 is chosen from the group containing leucine,
isoleucine, phenylalanine, alanine, valine, threonine and methionine;
[0216]X9 is chosen from the group containing glycine, alanine and serine;
[0217]X10 is chosen from the group containing isoleucine, valine and
asparagine; [0218]X11 is chosen from the group containing valine,
isoleucine and asparagine; [0219]X12 is chosen from the group containing
phenylalanine, tyrosine, isoleucine, valine, leucine and methionine;
[0220]X13 is chosen from the group containing isoleucine, valine,
leucine, methionine and phenylalanine; [0221]X14 is chosen from the group
containing threonine, glycine, alanine, serine and tyrosine; and
[0222]X15 is chosen from the group containing arginine, alanine, lysine,
glutamine, histidine and asparagine, or an amino acid deletion.

where: [0224]X1 is chosen from the group containing lysine, glutamine,
arginine, histidine and asparagine, or an amino acid deletion; [0225]X2
is chosen from the group containing glutaminic acid, asparaginic acid and
glutamine, or an amino acid deletion; [0226]X3 is chosen from the group
containing glycine, serine and alanine; [0227]X4 is chosen from the group
containing lysine, leucine and arginine; [0228]X5 is chosen from the
group containing serine, cysteine, glycine and threonine; [0229]X6 is
chosen from the group containing proline and alanine; [0230]X7 is chosen
from the group containing asparagine and glutamine; [0231]X8 is chosen
from the group containing leucine, isoleucine, phenylalanine, alanine,
valine, threonine and methionine; [0232]X9 is chosen from the group
containing glycine, alanine and serine; [0233]X10 is chosen from the
group containing isoleucine, valine and asparagine; [0234]X11 is chosen
from the group containing valine, isoleucine and asparagine; [0235]X12 is
chosen from the group containing phenylalanine, tyrosine, isoleucine,
valine, leucine and methionine; [0236]X13 is chosen from the group
containing isoleucine, valine, leucine, methionine and phenylalanine;
[0237]X14 is chosen from the group containing threonine, glycine,
alanine, serine and tyrosine; and [0238]X15 is chosen from the group
containing arginine, alanine, lysine, glutamine, histidine and
asparagine, or an amino acid deletion.

where: [0240]X1 is chosen from the group containing lysine, glutamine,
arginine, histidine and asparagine, or an amino acid deletion; [0241]X2
is chosen from the group containing glutaminic acid, asparaginic acid and
glutamine, or an amino acid deletion; [0242]X3 is chosen from the group
containing glycine, serine and alanine; [0243]X4 is chosen from the group
containing lysine, leucine and arginine; [0244]X5 is chosen from the
group containing serine, cysteine, glycine and threonine; [0245]X6 is
chosen from the group containing proline and alanine; [0246]X7 is chosen
from the group containing methionine, isoleucine, leucine, and
phenylalanine; [0247]X8 is chosen from the group containing leucine,
isoleucine, phenylalanine, alanine, valine, threonine and methionine;
[0248]X9 is chosen from the group containing glycine, alanine and serine;
[0249]X10 is chosen from the group containing isoleucine, valine and
asparagine; [0250]X11 is chosen from the group containing valine,
isoleucine and asparagine; [0251]X12 is chosen from the group containing
phenylalanine, tyrosine, isoleucine, valine, leucine and methionine;
[0252]X13 is chosen from the group containing isoleucine, valine,
leucine, methionine and phenylalanine; [0253]X14 is chosen from the group
containing threonine, glycine, alanine, serine and tyrosine; and
[0254]X15 is chosen from the group containing arginine, alanine, lysine,
glutamine, histidine and asparagine, or an amino acid deletion.

where: [0256]X1 is chosen from the group containing lysine, glutamine,
arginine, histidine and/or asparagine, or an amino acid deletion;
[0257]X2 is chosen from the group containing glutaminic acid, asparaginic
acid and/or glutamine, or an amino acid deletion; [0258]X3 is chosen from
the group containing glycine, serine and/or alanine; [0259]X4 is chosen
from the group containing lysine, leucine and/or arginine; [0260]X5 is
chosen from the group containing serine, cysteine, glycine and/or
threonine; [0261]X6 is chosen from the group containing serine, glycine
and/or threonine; [0262]X7 is chosen from the group containing asparagine
and/or glutamine; [0263]X8 is chosen from the group containing proline,
tyrosine and/or glycine; [0264]X9 is chosen from the group containing
glycine, alanine and/or serine; [0265]X10 is chosen from the group
containing isoleucine, valine and/or asparagine; [0266]X11 is chosen from
the group containing valine, isoleucine and/or asparagine; [0267]X12 is
chosen from the group containing phenylalanine, tyrosine, isoleucine,
valine, leucine and/or methionine; [0268]X13 is chosen from the group
containing isoleucine, valine, leucine, methionine and/or phenylalanine;
[0269]X14 is chosen from the group containing threonine, glycine,
alanine, serine and/or tyrosine; and [0270]X15 is chosen from the group
containing arginine, lysine, glutamine, histidine and/or asparagine, or
an amino acid deletion.

[0275]In some embodiments, the antagonist of PF4/RANTES interaction is a
fragment of any peptide sequence disclosed herein (hereinafter, "peptide
fragment"). As used herein, "peptide fragment" means an amino acid
polymer produced by cleaving any peptide of SEQ ID NO 1 through SEQ ID NO
44. In some embodiments, a peptide of SEQ ID NO 1 through SEQ ID NO 44 is
cleaved at one site (e.g., one peptide bond is broken). In some
embodiments, a peptide of SEQ ID NO 1 through SEQ ID NO 44 is cleaved at
two sites (e.g., two peptide bonds are broken). In some embodiments, the
peptide fragment is produced by the metabolism of any peptide of SEQ ID
NO 1 through SEQ ID NO 44.

[0276]In some embodiments, the fragment has structural features similar to
a peptide disclosed herein. In some embodiments, the fragment is linear.

[0277]In some embodiments, the fragment has between 5 and 10 amino acids.
In some embodiments, the fragment has 5 amino acids. In some embodiments,
the fragment has between 6 and 10 amino acids. In some embodiments, the
fragment has 6 amino acids. In some embodiments, the fragment has between
7 and 10 amino acids. In some embodiments, the fragment has between 8 and
10 amino acids. In some embodiments, the fragment has between 9 and 10
amino acids.

[0278]In some embodiments, the metabolite has a formula selected from:

whereinX1 is selected from serine and lysine;X2 is selected from glutamic
acid, phenylalanine and serine;X3 is selected from lysine and tyrosine;X4
is selected from phenylalanine and glycine;X5 is selected from threonine
and tyrosine;X6 is selected from serine and valine;X7 is selected from
serine and tyrosine;X8 is selected from alanine and lysine;X9 is selected
from leucine and serine;X10 is selected from leucine and valine;X11 is
selected from alanine and arginine;X12 is selected from serine and
valine;X13 is selected from valine and tyrosine;X14 is selected from
phenylalanine and serine;X15 is selected from phenylalanine and valine;
andX16 is selected from threonine and valine.

[0280]In some embodiments, any of the aforementioned peptides and/or
peptide fragments is used as a "model" to do structure-activity
relationship (SAR) chemistry. In some embodiments, the SAR chemistry
yields smaller peptides. In some embodiments, the smaller peptides yield
small molecules that disrupt the activity of RANTES and/or PF4 (e.g., by
figuring out the amino acid residues involved in disrupting the activity
of RANTES and/or PF4).

Peptide Mimetics

[0281]In some embodiments, a peptide mimetic is used in place of the
peptides described herein, including for use in the treatment or
prevention of the diseases disclosed herein.

[0282]Peptide mimetics (and peptide-based inhibitors) are developed using,
for example, computerized molecular modeling. Peptide mimetics are
designed to include structures having one or more peptide linkages
optionally replaced by a linkage selected from the group consisting of:
--CH2NH--, --CH2S--, --CH2--CH2--, --CH═CH-(cis
and trans), --CH═CF-(trans), --CoCH2--, --CH(OH)CH2--, and
--CH2SO--. In some embodiments such peptide mimetics have greater
chemical stability, enhanced pharmacological properties (half-life,
absorption, potency, efficacy, etc.), altered specificity (e.g., a
broad-spectrum of biological activities), reduced antigenicity, and are
more economically prepared. In some embodiments peptide mimetics include
covalent attachment of one or more labels or conjugates, directly or
through a spacer (e.g., an amide group), to non-interfering positions(s)
on the analog that are predicted by quantitative structure-activity data
and/or molecular modeling. Such non-interfering positions generally are
positions that do not form direct contacts with the receptor(s) to which
the peptide mimetic binds to produce the therapeutic effect. In some
embodiments, systematic substitution of one or more amino acids of a
consensus sequence with a D-amino acid of the same type (e.g., D-lysine
in place of L-lysine) are used to generate more stable peptides with
desired properties.

[0283]In some embodiments, a peptide mimetic is generated by use of a
phage display peptide libraries. For disclosure regarding the creation of
a phage display peptide library see Scott, J. K. et al. (1990) Science
249:386; Devlin, J. J. et al. (1990) Science 249:404; U.S. Pat. No.
5,223,409, U.S. Pat. No. 5,733,731; U.S. Pat. No. 5,498,530; U.S. Pat.
No. 5,432,018;U.S. Pat. No. 5,338,665;U.S. Pat. No. 5,922,545; WO
96/40987 and WO 98/15833 each of which is incorporated by reference for
such disclosure. In such libraries, random peptide sequences are
displayed by fusion with coat proteins of filamentous phage. Typically,
the displayed peptides are affinity-eluted against an
antibody-immobilized extracellular domain (in this case PF4 or RANTES. In
some embodiments peptide mimetics are isolated by biopanning In some
embodiments whole cells expressing PF4 or RANTES are used to screen the
library utilizing FACs to isolate phage bound cells. The retained phages
are enriched by successive rounds of biopanning and repropagation. The
best binding peptides are sequenced to identify key residues within one
or more structurally related families of peptides. The peptide sequences
also suggest which residues to replace by alanine scanning or by
mutagenesis at the DNA level. In some embodiments mutagenesis libraries
are created and screened to further optimize the sequence of the best
binders.

[0284]In some embodiments structural analysis of protein-protein
interaction is used to suggest peptides that mimic the binding activity
of the peptides described herein. In some embodiments the crystal
structure resulting from such an analysis suggests the identity and
relative orientation of critical residues of the peptide, from which a
peptide is designed.

[0285]For further disclosure re PF4/RANTES, methods of treatment
comprising inhibiting the interactions between PF4 and RANTES, and
pharmaceutical compositions comprising PF4 and RANTES antagonists see
U.S. Provisional Application 61/103,1872, filed Oct. 6, 2008; and PCT
International Publication No. WO 2007/042263, which are incorporated by
reference herein for such disclosures.

Combinations

[0286]Disclosed herein, in certain embodiments, are methods and
pharmaceutical compositions for modulating an inflammatory disorder
comprising co-administering (a) a therapeutically-effective amount of a
first active agent that inhibits the interaction between RANTES and
Platelet Factor 4; and (b) a therapeutically-effective amount of a second
active agent selected from an agent that treats an inflammatory disorder
through an alternative pathway.

[0287]In some embodiments, combining (a) the first active agent; and (b)
the second active agent is synergistic and results in a more efficacious
therapy. In some embodiments, the therapy is more efficacious as it
treats inflammatory disorders by multiple pathways. In some embodiments,
the therapy is more efficacious as it treats inflammatory disorders by
multiple pathways and treats and/or ameliorates undesired inflammation
resulting from the second agent. In some embodiments, the therapy is more
efficacious as it allows (partially or fully) a medical professional to
increase the prescribed dosage of the second active agent.

General Inflammatory Disorders

[0288]In some embodiments, the first active agent (i.e., a MIF antagonist
and/or a modulator of an interaction between RANTES and Platelet Factor
4), and a second anti-inflammatory agent, (e.g., an immunosuppressant)
synergistically treat an inflammatory disorder by (1) decreasing the
chemotaxis of leukocytes, and (2) reducing the influx of cytokines.

[0291]In some embodiments, the first active agent and a 5-ASA treat an
inflammatory disorder by (1) decreasing the chemotaxis of leukocytes, and
(2) reducing the synthesis of eicosanoids and inflammatory cytokines In
some embodiments, the first active agent also decreases any undesired
inflammation (e.g., pancreatitis) resulting from administration of the
5-ASA.

[0292]In some embodiments, the first active agent and an anti-TNF agent
treat an inflammatory disorder by (1) decreasing the chemotaxis of
leukocytes, and (2) suppressing a TNF-induced cytokine cascade. In some
embodiments, the first active agent also decreases any undesired
inflammation (e.g., tuberculosis) resulting from administration of the
anti-TNF agent.

[0293]In some embodiments, the first active and a leukotriene inhibitor
treat an inflammatory disorder by (1) decreasing the chemotaxis of
leukocytes, and (2) antagonizing LTA4, LTB4, LTC4, LTD4, LTE4, LTF4,
LTA4R; LTB4R; LTB4R1, LTB4R2, LTC4R, LTD4R, LTE4R, CYSLTR1, or CYSLTR2;
or inhibiting the synthesis of a leukotriene via 5-LO, FLAP, LTA4H,
LTA4S, or LTC4S. In some embodiments, the first active agent also
decreases any undesired inflammation (e.g., tuberculosis) resulting from
administration of the leukotriene inhibitor.

[0294]In some embodiments, the first active agent and an IL-1 receptor
antagonist treat an inflammatory disorder by (1) decreasing the
chemotaxis of leukocytes, and (2) blocking the stimulation of T cell IL-1
receptor. In some embodiments, the first active agent also decreases any
undesired inflammation (e.g., pneumonia, and bone and joint infections)
resulting from administration of the IL-1 receptor antagonist.

[0295]In some embodiments, the first active agent and an IL-2 receptor
antagonist treat an inflammatory disorder by (1) decreasing the
chemotaxis of leukocytes, and (2) blocking the stimulation of T cell IL-2
receptor. In some embodiments, the first active agent also decreases any
undesired inflammation (e.g., gastrointestinal disorders) resulting from
administration of the IL-2 receptor antagonist.

[0296]In some embodiments, the first active agent and a cytotoxic agent
treat an inflammatory disorder by (1) decreasing the chemotaxis of
leukocytes, and (2) treating neoplastic disease. In some embodiments, the
first active agent also decreases any undesired inflammation (e.g.,
neutropenia) resulting from administration of the cytotoxic agent.

[0297]In some embodiments, the first active agent and an immunomodulatory
agent treat an inflammatory disorder by (1) decreasing the chemotaxis of
leukocytes, and (2) enhancing, or suppressing the immune system. In some
embodiments, the first active agent also decreases any undesired
inflammation (e.g., hematologic side effects) resulting from
administration of the immunomodulatory agent.

[0298]In some embodiments, the first active agent (and an antibiotic treat
an inflammatory disorder by (1) decreasing the chemotaxis of leukocytes,
and (2) by blocking cell and/or microbial growth by disrupting the cell
cycle, or by blocking histone deacetylase. In some embodiments, the first
active agent also decreases any undesired inflammation (e.g.,
cardiotoxicity) resulting from administration of the antibiotic.

[0299]In some embodiments, the first active agent and a T-cell
co-stimulatory blocker treat an inflammatory disorder by (1) decreasing
the chemotaxis of leukocytes, and (2) modulating a co-stimulatory signal
which is required for full T-cell activation. In some embodiments, the
first active agent also decreases any undesired inflammation (e.g.,
neutropenia) resulting from administration of the T-cell co-stimulatory
blocker.

[0300]In some embodiments, the first active agent and a B cell depleting
agent treat an inflammatory disorder by (1) decreasing the chemotaxis of
leukocytes, and (2) inhibits B-cell activity. In some embodiments, the
first active agent also decreases any undesired inflammation (e.g.,
Progressive Multifocal Leukoencephalopathy) resulting from administration
of the B-cell depleting agent.

[0301]In some embodiments, the first active agent and an immunosuppressive
agent treat an inflammatory disorder by (1) decreasing the chemotaxis of
leukocytes, and (2) selectively or non-selectively inhibits or prevents
activity of the immune system. In some embodiments, the first active
agent also decreases any undesired inflammation (e.g., lymphoma)
resulting from administration of immunosuppressive agent.

[0302]In some embodiments, the first active agent and an alkylating agent
treat an inflammatory disorder by (1) decreasing the chemotaxis of
leukocytes, and (2) inducing covalent binding of alkyl groups to cellular
molecules. In some embodiments, the first active agent also decreases any
undesired inflammation (e.g., immune suppression) resulting from
administration of the alkylating agent.

[0303]In some embodiments, the first active agent and an anti-metabolite
treat an inflammatory disorder by (1) decreasing the chemotaxis of
leukocytes, and (2) preventing the biosynthesis or use of normal cellular
metabolites. In some embodiments, the first active agent also decreases
any undesired inflammation (e.g., mutagenesis) resulting from
administration of the anti metabolite.

[0304]In some embodiments, the first active agent and a plant alkaloid
treat an inflammatory disorder by (1) decreasing the chemotaxis of
leukocytes, and (2) interfering with normal microtubule breakdown during
cell division. In some embodiments, the first active agent also decreases
any undesired inflammation (e.g., leukopenia) resulting from
administration of the plant alkaloid.

[0305]In some embodiments, the first active agent and a terpenoid treat an
inflammatory disorder by (1) decreasing the chemotaxis of leukocytes, and
(2) treating neoplastic disease or microbial infections. In some
embodiments, the first active agent also decreases any undesired
inflammation resulting from administration of the terpenoid agent.

[0306]In some embodiments, the first active agent and a topoisomerase
inhibitor treat an inflammatory disorder by (1) decreasing the chemotaxis
of leukocytes, and (2) modulating the action of cellular topoisomerase
enzymes. In some embodiments, the first active agent also decreases any
undesired inflammation (e.g., gastrointestinal effects) resulting from
administration of the topoisomerase inhibitor.

[0307]In some embodiments, the first active agent and an antibody treat an
inflammatory disorder by (1) decreasing the chemotaxis of leukocytes, and
(2) neutralizing inflammatory cytokines such as, for example, TNF alpha.
In some embodiments, the first active agent also decreases any undesired
inflammation (e.g., tuberculosis) resulting from administration of the
antibody.

[0308]In some embodiments, the first active agent and a hormonal therapy
treat an inflammatory disorder by (1) decreasing the chemotaxis of
leukocytes, and (2) suppressing cytokine release. In some embodiments,
the first active agent also decreases any undesired inflammation (e.g.,
cancer) resulting from administration of the hormone.

[0309]In some embodiments, the first active agent and an anti-diabetes
therapy treat an inflammatory disorder by (1) decreasing the chemotaxis
of leukocytes, and (2) improving sensitivity to insulin in muscle and
adipose tissue. In some embodiments, the first active agent also
decreases any undesired inflammation (e.g., liver inflammation,
pancreatitis) resulting from administration of the anti-diabetes agent.

Cardiovascular Disorders

[0310]In some embodiments, the second active agent is selected from an
agent that treats a cardiovascular disorder (the "cardiovascular disorder
agent"). In some embodiments, the first active agent rescues a mammal
from inflammation partially or fully caused by the cardiovascular
disorder agent.

[0312]In some embodiments, the cardiovascular disorder agent raises HDL
non-selectively. In some embodiments, the cardiovascular disorder agent
down-regulates transcription of a CETP gene. In some embodiments, the
second active agent is niacin.

[0313]In some embodiments, the cardiovascular disorder agent is a statin.
In some embodiments, the cardiovascular disorder agent is atorvastatin;
cerivastatin; fluvastatin; lovastatin; mevastatin; pitavastatin;
pravastatin; rosuvastatin; simvastatin; simvastatin and ezetimibe;
lovastatin and niacin, extended-release; atorvastatin and amlodipine
besylate; simvastatin and niacin, extended-release; or combinations
thereof. In some embodiments, the first active agent and the statin
synergistically treat a CVD by (1) decreasing the chemotaxis of
leukocytes, (2) decreasing the synthesis of cholesterol, and (3)
decreasing any undesired inflammation resulting from administration of
the statin. In certain instances, statins induce inflammation. In certain
instances, administration of a statin results (partially or fully) in
myositis. In certain instances, statin-induced myositis is
dose-dependent. In some embodiments, prescribing the first active agent
allows (partially or fully) a medical professional to increase the
prescribed dosage of statin.

[0314]In some embodiments, the cardiovascular disorder agent reduces the
risk of developing a cardiovascular disorder in individuals with low HDL
with metabolic syndrome. In some embodiments, the cardiovascular disorder
agent is a fibrate. In some embodiments, the cardiovascular disorder
agent is bezafibrate; ciprofibrate; clofibrate; gemfibrozil; fenofibrate;
or combinations thereof. In some embodiments, the first active agent and
the fibrate synergistically treat a CVD by (1) decreasing the chemotaxis
of leukocytes, and (2) increasing the concentration of HDL. In some
embodiments, the first active agent also decreases any undesired
inflammation resulting from administration of the fibrate.

[0315]In some embodiments, the cardiovascular disorder agent selectively
increases the levels of ApoA-I protein (e.g. by transcriptional induction
of the gene encoding ApoA-I) and increases the production of nascent HDL
(ApoAI-enriched). In some embodiments, the cardiovascular disorder agent
is DF4 (Ac-D-W--F--K-A-F--Y-D-K--V-A-E-K--F--K-E-A-F--NH2); DF5; RVX-208
(Resverlogix); or combinations thereof. In some embodiments, the first
active agent and the ApoA1 modulator synergistically treat a CVD by (1)
decreasing the chemotaxis of leukocytes, and (2) increasing the
concentration of HDL. In some embodiments, the first active agent also
decreases any undesired inflammation resulting from administration of the
ApoA1 modulator.

[0317]In some embodiments, the cardiovascular disorder agent (partially or
completely) the inhibits activity of Cholesteryl Ester Transfer Protein
(CETP). In some embodiments, the cardiovascular disorder agent is
torcetrapib; anacetrapid; JTT-705 (Japan Tobacco/Roche); or combinations
thereof. In some embodiments, the first active agent and the CETP
modulator synergistically treat a CVD by (1) decreasing the chemotaxis of
leukocytes, and (2) decreasing the transfer cholesterol from HDL
cholesterol to LDL. In some embodiments, the first active agent also
decreases any undesired inflammation resulting from administration of the
CETP inhibitor.

[0319]In some embodiments, the cardiovascular disorder agent is a
Glycoprotein (GP) IIb/IIIa receptor antagonist. In some embodiments, the
cardiovascular disorder agent is abciximab; eptifibatide; tirofiban;
roxifiban; variabilin; XV 459
(N(3)-(2-(3-(4-formamidinophenyl)isoxazolin-5-yl)acetyl)-N(2)-(1-butyloxy-
carbonyl)-2,3-diaminopropionate); SR 121566A
(3-[N-{4-[4-(aminoiminomethyl)phenyl]-1,3-thiazol-2-yl}-N-(1-carboxymethy-
lpiperid-4-yl) amino]propionic acid, trihydrochloride); FK419
((S)-2-acetylamino-3-[(R)-[1-[3-(piperidin-4-yl)
propionyl]piperidin-3-ylcarbonyl]amino]propionic acid trihydrate); or
combinations thereof. In some embodiments, the first active agent and the
GP IIb/IIIa receptor antagonist synergistically treat a CVD by (1)
decreasing the chemotaxis of leukocytes, and (2) inhibiting platelet
aggregation. In some embodiments, the first active agent also decreases
any undesired inflammation resulting from administration of the GP
IIb/IIIa receptor antagonist.

[0320]In some embodiments, the cardiovascular disorder agent is a P2Y12
receptor antagonist. In some embodiments, the cardiovascular disorder
agent is clopidogrel; prasugrel; cangrelor; AZD6140 (AstraZeneca); MRS
2395 (2,2-Dimethyl-propionic acid
3-(2-chloro-6-methylaminopurin-9-yl)-2-(2,2-dimethyl-propionyloxymethyl)--
propyl ester); BX 667 (Berlex Biosciences); BX 048 (Berlex Biosciences) or
combinations thereof. In some embodiments, the first active agent and the
P2Y12 receptor antagonist synergistically treat a CVD by (1) decreasing
the chemotaxis of leukocytes, and (2) inhibiting platelet aggregation. In
some embodiments, the first active agent also decreases any undesired
inflammation resulting from administration of the P2Y12 receptor
antagonist.

[0321]In some embodiments, the cardiovascular disorder agent is an Lp-PLA2
antagonist. In some embodiments, the second active agent is darapladib
(SB 480848); SB-435495 (GlaxoSmithKline); SB-222657 (GlaxoSmithKline);
SB-253514 (GlaxoSmithKline); or combinations thereof. In some
embodiments, the first active agent and Lp-PLA2 antagonist
synergistically treat a CVD by (1) decreasing the chemotaxis of
leukocytes, and (2) inhibiting the formation of biologically active
products from oxidized LDL. In some embodiments, the first active agent
also decreases any undesired inflammation resulting from administration
of the Lp-PLA2 antagonist.

[0322]In some embodiments, the cardiovascular disorder agent is a
leukotriene (e.g., LTA4, LTB4, LTC4, LTD4, LTE4, and LTF4) inhibitor
(e.g., an antagonist of 5-LO, FLAP, LTA4H, LTA4S, LTA4R; LTB4R; LTB4R1,
LTB4R2, LTC4S, LTC4R, LTD4R, LTE4R, CYSLTR1, or CYSLTR2). In some
embodiments, the second active agent is an antagonist of 5-LO. In some
embodiments, the second active agent is an antagonist of FLAP. In some
embodiments, the second active agent is A-81834
(3-(3-(1,1-dimethylethylthio-5-(quinoline-2-ylmethoxy)-1-(4-chloromethylp-
henyl)indole-2-yl)-2,2-dimethylpropionaldehyde oxime-O-2-acetic acid;
AM103 (Amira); AM803 (Amira); atreleuton; BAY-x-1005
((R)-(+)-alpha-cyclopentyl-4-(2-quinolinylmethoxy)-Benzeneacetic acid);
CJ-13610 (4-(3-(4-(2-Methyl-imidazol-1-yl)-phenylsulfanyl)-phenyl)-tetrah-
ydro-pyran-4-carboxylic acid amide); DG-031 (DeCode); DG-051 (DeCode);
MK886 (1-[(4-chlorophenyl)methyl]3-[(1,1-dimethylethyl)thio]-α,.alp-
ha.-dimethyl-5-(1-methylethyl)-1H-indole-2-propanoic acid, sodium salt);
MK591 (3-(1-4[(4-chlorophenyl)methyl]-3-[t-butylthio)-5-((2-quinoly)metho-
xy)-1H-indole-2]-, dimethylpropanoic acid); RP64966
([4-[5-(3-Phenyl-propyl)thiophen-2-yl]butoxy]acetic acid); SA6541
((R)--S-[[4-(dimethylamino)phenyl]methyl]-N-(3-mercapto-2-methyl-1-oxopro-
pyl-L-cycteine); SC-56938
(ethyl-1-[2-[4-(phenylmethyl)phenoxy]ethyl]-4-piperidine-carboxylate);
VIA-2291 (Via Pharmaceuticals); WY-47,288
(2-[(1-naphthalenyloxy)methyl]quinoline); zileuton; ZD-2138
(6-((3-fluoro-5-(tetrahydro-4-methoxy-2H-pyran-4-yl)phenoxy)methyl)-1-met-
hyl-2(1H)-quinlolinone); or combinations thereof. In some embodiments, the
first active agent (i.e., a MIF antagonist and/or a modulator of an
interaction between RANTES and Platelet Factor 4) and a leukotriene
antagonist synergistically treat a CVD by (1) decreasing the chemotaxis
of leukocytes, and (2) inhibiting the adhesion and activation of
leukocytes on the endothelium, decreasing the chemotaxis of neutrophils
and reducing the formation of reactive oxygen species. In some
embodiments, the first active agent also decreases any undesired
inflammation resulting from administration of the leukotriene antagonist.

Gene Therapy

[0323]In some embodiments, are methods and pharmaceutical compositions for
modulating a disorder of a cardiovascular system, comprising a
synergistic combination of (a) a therapeutically-effective amount of a
first active agent selected from (1) a modulator of MIF; (2) a modulator
of an interaction between RANTES and Platelet Factor 4; or (3)
combinations thereof and (b) gene therapy.

[0324]In some embodiments, the gene therapy comprises modulating the
concentration of a lipid and/or lipoprotein (e.g., HDL) in the blood of
an individual in need thereof. In some embodiments, modulating the
concentration of a lipid and/or lipoprotein (e.g., HDL) in the blood
comprises transfecting DNA into an individual in need thereof. In some
embodiments, the DNA encodes an Apo A1 gene, an LCAT gene, and/or an LDL
gene. In some embodiments, the DNA is transfected into a liver cell.

[0325]In some embodiments, the DNA is transfected into a liver cell via
use of ultrasound. For disclosures of techniques related to transfecting
ApoA1 DNA via use of ultrasound see U.S. Pat. No. 7,211,248, which is
hereby incorporated by reference for those disclosures.

[0326]In some embodiments, an individual is administered a vector
engineered to carry the human gene (the "gene vector"). For disclosures
of techniques for creating an LDL gene vector see U.S. Pat. No.
6,784,162, which is hereby incorporated by reference for those
disclosures. In some embodiments, the gene vector is a retrovirus. In
some embodiments, the gene vector is not a retrovirus (e.g. it is an
adenovirus; a lentivirus; or a polymeric delivery system such as
METAFECTENE, SUPERFECT®, EFFECTENE®, or MIRUS TRANSIT). In
certain instances, a retrovirus, adenovirus, or lentivirus will have a
mutation such that the virus is rendered incompetent.

[0327]In some embodiments, the vector is administered in vivo (i.e., the
vector is injected directly into the individual, for example into a liver
cell), ex vivo (i.e., cells from the individual are grown in vitro and
transduced with the gene vector, embedded in a carrier, and then
implanted in the individual), or a combination thereof.

[0328]In certain instances, after administration of the gene vector, the
gene vector infects the cells at the site of administration (e.g. the
liver). In certain instances the gene sequence is incorporated into the
subject's genome (e.g. when the gene vector is a retrovirus). In certain
instances the therapy will need to be periodically re-administered (e.g.
when the gene vector is not a retrovirus). In some embodiments, the
therapy is re-administered annually. In some embodiments, the therapy is
re-administered semi-annually. In some embodiments, the therapy is
re-administered when the subject's HDL level decreases below about 60
mg/dL. In some embodiments, the therapy is re-administered when the
subject's HDL level decreases below about 50 mg/dL. In some embodiments,
the therapy is re-administered when the subject's HDL level decreases
below about 45 mg/dL. In some embodiments, the therapy is re-administered
when the subject's HDL level decreases below about 40 mg/dL. In some
embodiments, the therapy is re-administered when the subject's HDL level
decreases below about 35 mg/dL. In some embodiments, the therapy is
re-administered when the subject's HDL level decreases below about 30
mg/dL.

RNAi Therapies

[0329]In some embodiments, are methods and pharmaceutical compositions for
modulating a disorder of a cardiovascular system, comprising a
synergistic combination of (a) a therapeutically-effective amount of a
first active agent selected from (1) a modulator of MIF; (2) a modulator
of an interaction between RANTES and Platelet Factor 4; or (3)
combinations thereof; and (b) silencing the expression of a gene that
increases the concentration of a lipid in blood (the "target gene"). In
some embodiments, the target gene is Apolipoprotein B (Apo B), Heat Shock
Protein 110 (Hsp 110), and Proprotein Convertase Subtilisin Kexin 9
(Pcsk9) (ALN-PCS, BMS-PCSK9Rx). In some embodiments, the target gene
is C-reactive protein (CRP) (ISIS-CRPRx).

[0330]In some embodiments, the target gene is silenced by RNA interference
(RNAi). In some embodiments, the RNAi therapy comprises use of an siRNA
molecule. In some embodiments, a double stranded RNA (dsRNA) molecule
with sequences complementary to an mRNA sequence of a gene to be silenced
(e.g., Apo B, Hsp 110 and Pcsk9) is generated (e.g by PCR). In some
embodiments, a 20-25 by siRNA molecule with sequences complementary to an
mRNA sequence of a gene to be silenced is generated. In some embodiments,
the 20-25 by siRNA molecule has 2-5 by overhangs on the 3' end of each
strand, and a 5' phosphate terminus and a 3' hydroxyl terminus. In some
embodiments, the 20-25 by siRNA molecule has blunt ends. For techniques
for generating RNA sequences see Molecular Cloning: A Laboratory Manual,
second edition (Sambrook et al., 1989) and Molecular Cloning: A
Laboratory Manual, third edition (Sambrook and Russel, 2001), jointly
referred to herein as "Sambrook"); Current Protocols in Molecular Biology
(F. M. Ausubel et al., eds., 1987, including supplements through 2001);
Current Protocols in Nucleic Acid Chemistry John Wiley & Sons, Inc., New
York, 2000) which are hereby incorporated by reference for such
disclosure.

[0331]In some embodiments, an siRNA molecule is "fully complementary"
(i.e., 100% complementary) to the target gene. In some embodiments, an
antisense molecule is "mostly complementary" (e.g., 99%, 98%, 97%, 96%,
95%, 94%, 93%, 92%, 91%, 90%, 85%, 80%, 75%, or 70% complementary) to the
target gene. In some embodiments, there is a 1 by mismatch, a 2 by
mismatch, a 3 by mismatch, a 4 by mismatch, or a 5 by mismatch.

[0332]In certain instances, after administration of the dsRNA or siRNA
molecule, cells at the site of administration (e.g. the cells of the
liver and/or small intestine) are transformed with the dsRNA or siRNA
molecule. In certain instances following transformation, the dsRNA
molecule is cleaved into multiple fragments of about 20-25 by to yield
siRNA molecules. In certain instances, the fragments have about 2 bp
overhangs on the 3' end of each strand.

[0333]In certain instances, an siRNA molecule is divided into two strands
(the guide strand and the anti-guide strand) by an RNA-induced Silencing
Complex (RISC). In certain instances, the guide strand is incorporated
into the catalytic component of the RISC (i.e. argonaute). In certain
instances, the guide strand binds to a complementary RB1 mRNA sequence.
In certain instances, the RISC cleaves an mRNA sequence of a gene to be
silenced. In certain instances, the expression of the gene to be silenced
is down-regulated.

[0334]In some embodiments, a sequence complementary to an mRNA sequence of
a target gene is incorporated into a vector. In some embodiments, the
sequence is placed between two promoters. In some embodiments, the
promoters are orientated in opposite directions. In some embodiments, the
vector is contacted with a cell. In certain instances, a cell is
transformed with the vector. In certain instances following
transformation, sense and anti-sense strands of the sequence are
generated. In certain instances, the sense and anti-sense strands
hybridize to form a dsRNA molecule which is cleaved into siRNA molecules.
In certain instances, the strands hybridize to form an siRNA molecule. In
some embodiments, the vector is a plasmid (e.g pSUPER; pSUPER.neo;
pSUPER.neo+gfp).

[0335]In some embodiments, an siRNA molecule is administered in vivo
(i.e., the vector is injected directly into the individual, for example
into a liver cell or a cell of the small intestine, or into the blood
stream).

[0338]In some embodiments, an siRNA molecule described herein is
administered iontophoretically, for example to a particular organ or
compartment (e.g., the liver or small intestine). Non-limiting examples
of iontophoretic delivery are described in, for example, WO 03/043689 and
WO 03/030989, which are hereby incorporated by reference for such
disclosures.

[0339]In some embodiments, an siRNA molecule described herein is
administered systemically (i.e., in vivo systemic absorption or
accumulation of an siRNA molecule in the blood stream followed by
distribution throughout the entire body). Administration routes
contemplated for systemic administration include, but are not limited to,
intravenous, subcutaneous, portal vein, intraperitoneal, and
intramuscular. Each of these administration routes exposes the siRNA
molecules of the invention to an accessible diseased tissue (e.g.,
liver).

[0340]In certain instances the therapy will need to be periodically
re-administered. In some embodiments, the therapy is re-administered
annually. In some embodiments, the therapy is re-administered
semi-annually. In some embodiments, the therapy is administered monthly.
In some embodiments, the therapy is administered weekly. In some
embodiments, the therapy is re-administered when the subject's HDL level
decreases below about 60 mg/dL. In some embodiments, the therapy is
re-administered when the subject's HDL level decreases below about 50
mg/dL. In some embodiments, the therapy is re-administered when the
subject's HDL level decreases below about 45 mg/dL. In some embodiments,
the therapy is re-administered when the subject's HDL level decreases
below about 40 mg/dL. In some embodiments, the therapy is re-administered
when the subject's HDL level decreases below about 35 mg/dL. In some
embodiments, the therapy is re-administered when the subject's HDL level
decreases below about 30 mg/dL.

[0341]For disclosures of techniques related to silencing the expression of
Apo B and/or Hsp110 see U.S. Pub. No. 2007/0293451 which is hereby
incorporated by reference for such disclosures. For disclosures of
techniques related to silencing the expression of Pcsk9 see U.S. Pub. No.
2007/0173473, which is hereby incorporated by reference for such
disclosures.

Antisense Therapies

[0342]In some embodiments, are methods and pharmaceutical compositions for
modulating a disorder of a cardiovascular system, comprising a
synergistic combination of (a) a therapeutically-effective amount of a
first active agent selected from (1) a modulator of MIF; (2) a modulator
of an interaction between RANTES and Platelet Factor 4; or (3)
combinations thereof; and (b) inhibiting the expression of and/or
activity of an RNA sequence that increases the concentration of a lipid
in blood (the "target sequence"). In some embodiments, inhibiting the
expression of and/or activity of a target sequence comprises use of an
antisense molecule complementary to the target sequence. In some
embodiments, the target sequence is microRNA-122 (miRNA-122 or mRNA-122).
In certain instances, inhibiting the expression of and/or activity of
miRNA-122 results (partially or fully) in a decrease in the concentration
of cholesterol and/or lipids in blood.

[0343]In some embodiments, an antisense molecule that is complementary to
a target sequence is generated (e.g. by PCR). In some embodiments, the
antisense molecule is about 15 to about 30 nucleotides. In some
embodiments, the antisense molecule is about 17 to about 28 nucleotides.
In some embodiments, the antisense molecule is about 19 to about 26
nucleotides. In some embodiments, the antisense molecule is about 21 to
about 24 nucleotides. For techniques for generating RNA sequences see
Molecular Cloning: A Laboratory Manual, second edition (Sambrook et al.,
1989) and Molecular Cloning: A Laboratory Manual, third edition (Sambrook
and Russel, 2001), jointly referred to herein as "Sambrook"); Current
Protocols in Molecular Biology (F. M. Ausubel et al., eds., 1987,
including supplements through 2001); Current Protocols in Nucleic Acid
Chemistry John Wiley & Sons, Inc., New York, 2000) which are hereby
incorporated by reference for such disclosure.

[0344]In some embodiments, the antisense molecules are single-stranded,
double-stranded, circular or hairpin. In some embodiments, the antisense
molecules contain structural elements (e.g., internal or terminal bulges,
or loops).

[0345]In some embodiments, an antisense molecule is "fully complementary"
(i.e., 100% complementary) to the target sequence. In some embodiments,
an antisense molecule is "mostly complementary" (e.g., 99%, 98%, 97%,
96%, 95%, 94%, 93%, 92%, 91%, 90%, 85%, 80%, 75%, or 70% complementary)
to the target RNA sequence. In some embodiments, there is a 1 by
mismatch, a 2 by mismatch, a 3 by mismatch, a 4 by mismatch, or a 5 by
mismatch.

[0346]In some embodiments, the antisense molecule hybridizes to the target
sequence. As used herein, "hybridize" means the pairing of nucleotides of
an antisense molecule with corresponding nucleotides of the target
sequence. In certain instances, hybridization involves the formation of
one or more hydrogen bonds (e.g., Watson-Crick, Hoogsteen or reversed
Hoogsteen hydrogen bonding) between the pairing nucleotides.

[0350]In some embodiments, an siRNA molecule described herein is
administered iontophoretically, for example to a particular organ or
compartment (e.g., the liver or small intestine). Non-limiting examples
of iontophoretic delivery are described in, for example, WO 03/043689 and
WO 03/030989, which are hereby incorporated by reference for such
disclosures.

[0351]In some embodiments, an siRNA molecule described herein is
administered systemically (i.e., in vivo systemic absorption or
accumulation of an siRNA molecule in the blood stream followed by
distribution throughout the entire body). Administration routes
contemplated for systemic administration include, but are not limited to,
intravenous, subcutaneous, portal vein, intraperitoneal, and
intramuscular. Each of these administration routes exposes the siRNA
molecules of the invention to an accessible diseased tissue (e.g.,
liver).

[0352]In certain instances the therapy will need to be periodically
re-administered. In some embodiments, the therapy is re-administered
annually. In some embodiments, the therapy is re-administered
semi-annually. In some embodiments, the therapy is administered monthly.
In some embodiments, the therapy is administered weekly. In some
embodiments, the therapy is re-administered when the subject's HDL level
decreases below about 60 mg/dL. In some embodiments, the therapy is
re-administered when the subject's HDL level decreases below about 50
mg/dL. In some embodiments, the therapy is re-administered when the
subject's HDL level decreases below about 45 mg/dL. In some embodiments,
the therapy is re-administered when the subject's HDL level decreases
below about 40 mg/dL. In some embodiments, the therapy is re-administered
when the subject's HDL level decreases below about 35 mg/dL. In some
embodiments, the therapy is re-administered when the subject's HDL level
decreases below about 30 mg/dL.

[0353]For disclosures of techniques related to silencing the expression of
miRNA-122 see WO 07/027,775A2, which is hereby incorporated by reference
for such disclosures.

Device-Mediated Therapies

[0354]In some embodiments, the device mediated strategy comprises removing
a lipid from an HDL molecule in an individual in need thereof
(delipidation), removing an LDL molecule from the blood or plasma of an
individual in need thereof (delipidation), or a combination thereof. For
disclosures of techniques for removing a lipid from an HDL molecule and
removing an LDL molecule from the blood or plasma of an individual in
need thereof see U.S. Pub. No. 2008/0230465, which is hereby incorporated
by reference for those disclosures.

[0355]In certain instances, the delipidation therapy will need to be
periodically re-administered. In some embodiments, the delipidation
therapy is re-administered annually. In some embodiments, the
delipidation therapy is re-administered semi-annually. In some
embodiments, the delipidation therapy is re-administered monthly. In some
embodiments, the delipidation therapy is re-administered semi-weekly. In
some embodiments, the therapy is re-administered when the subject's HDL
level decreases below about 60 mg/dL. In some embodiments, the therapy is
re-administered when the subject's HDL level decreases below about 50
mg/dL. In some embodiments, the therapy is re-administered when the
subject's HDL level decreases below about 45 mg/dL. In some embodiments,
the therapy is re-administered when the subject's HDL level decreases
below about 40 mg/dL. In some embodiments, the therapy is re-administered
when the subject's HDL level decreases below about 35 mg/dL. In some
embodiments, the therapy is re-administered when the subject's HDL level
decreases below about 30 mg/dL.

Pharmaceutical Compositions

[0356]Disclosed herein, in certain embodiments, is a pharmaceutical
composition for modulating a disorder of a cardiovascular system,
comprising a synergistic combination of (a) a therapeutically-effective
amount of a first active agent that inhibits interactions between RANTES
and Platelet Factor 4; and (b) a second active agent selected from an
agent that treats cardiovascular disorders.

[0358]In certain embodiments, the pharmaceutical composition for
modulating a disorder of a cardiovascular system further comprises a
pharmaceutically acceptable diluent(s), excipient(s), or carrier(s). In
some embodiments, the pharmaceutical compositions includes other
medicinal or pharmaceutical agents, carriers, adjuvants, such as
preserving, stabilizing, wetting or emulsifying agents, solution
promoters, salts for regulating the osmotic pressure, and/or buffers. In
addition, the pharmaceutical compositions also contain other
therapeutically valuable substances.

[0361]In some embodiments, the pharmaceutical compositions described
herein are formulated as mulitparticulate formulations. In some
embodiments, the pharmaceutical compositions described herein comprise a
first population of particles and a second population of particles. In
some embodiments, the first population comprises an active agent. In some
embodiments, the second population comprises an active agent. In some
embodiments, the dose of active agent in the first population is equal to
the dose of active agent in the second population. In some embodiments,
the dose of active agent in the first population is not equal to (e.g.,
greater than or less than) the dose of active agent in the second
population.

[0362]In some embodiments, the active agent of the first population is
released before the active agent of the second population. In some
embodiments, the second population of particles comprises a
modified-release (e.g., delayed-release, controlled-release, or extended
release) coating. In some embodiments, the second population of particles
comprises a modified-release (e.g., delayed-release, controlled-release,
or extended release) matrix.

[0365]In some embodiments, the first population of particles comprises a
cardiovascular disorder agent. In some embodiments, the second population
of particles comprises a (1) a modulator of MIF; (2) a modulator of an
interaction between RANTES and Platelet Factor 4; or (3) combinations
thereof. In some embodiments, the first population of particles comprises
a (1) a modulator of MIF; (2) a modulator of an interaction between
RANTES and Platelet Factor 4; or (3) combinations thereof. In some
embodiments, the second population of particles comprises a
cardiovascular disorder agent.

[0367]In some embodiments, the solid dosage forms disclosed herein are in
the form of a tablet, (including a suspension tablet, a fast-melt tablet,
a bite-disintegration tablet, a rapid-disintegration tablet, an
effervescent tablet, or a caplet), a pill, a powder (including a sterile
packaged powder, a dispensable powder, or an effervescent powder) a
capsule (including both soft or hard capsules, e.g., capsules made from
animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules"),
solid dispersion, solid solution, bioerodible dosage form, controlled
release formulations, pulsatile release dosage forms, multiparticulate
dosage forms, pellets, granules, or an aerosol. In other embodiments, the
pharmaceutical formulation is in the form of a powder. In still other
embodiments, the pharmaceutical formulation is in the form of a tablet,
including but not limited to, a fast-melt tablet. Additionally,
pharmaceutical formulations disclosed herein are optionally administered
as a single capsule or in multiple capsule dosage form. In some
embodiments, the pharmaceutical formulation is administered in two, or
three, or four, capsules or tablets.

[0368]In another aspect, dosage forms include microencapsulated
formulations. In some embodiments, one or more other compatible materials
are present in the microencapsulation material. Exemplary materials
include, but are not limited to, pH modifiers, erosion facilitators,
anti-foaming agents, antioxidants, flavoring agents, and carrier
materials such as binders, suspending agents, disintegration agents,
filling agents, surfactants, solubilizers, stabilizers, lubricants,
wetting agents, and diluents.

[0371]In some embodiments, the pharmaceutical formulations described
herein are elf-emulsifying drug delivery systems (SEDDS). Emulsions are
dispersions of one immiscible phase in another, usually in the form of
droplets. Generally, emulsions are created by vigorous mechanical
dispersion. SEDDS, as opposed to emulsions or microemulsions,
spontaneously form emulsions when added to an excess of water without any
external mechanical dispersion or agitation. An advantage of SEDDS is
that only gentle mixing is required to distribute the droplets throughout
the solution. Additionally, water or the aqueous phase is optionally
added just prior to administration, which ensures stability of an
unstable or hydrophobic active ingredient. Thus, the SEDDS provides an
effective delivery system for oral and parenteral delivery of hydrophobic
active ingredients. In some embodiments, SEDDS provides improvements in
the bioavailability of hydrophobic active ingredients. Methods of
producing self-emulsifying dosage forms include, but are not limited to,
for example, U.S. Pat. Nos. 5,858,401, 6,667,048, and 6,960,563.

[0372]Suitable intranasal formulations include those described in, for
example, U.S. Pat. Nos. 4,476,116, 5,116,817 and 6,391,452. Nasal dosage
forms generally contain large amounts of water in addition to the active
ingredient. Minor amounts of other ingredients such as pH adjusters,
emulsifiers or dispersing agents, preservatives, surfactants, gelling
agents, or buffering and other stabilizing and solubilizing agents are
optionally present.

[0373]For administration by inhalation, the pharmaceutical compositions
disclosed herein are optionally in a form of an aerosol, a mist or a
powder. Pharmaceutical compositions described herein are conveniently
delivered in the form of an aerosol spray presentation from pressurized
packs or a nebuliser, with the use of a suitable propellant, e.g.,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the
case of a pressurized aerosol, the dosage unit is determined by providing
a valve to deliver a metered amount. Capsules and cartridges of, such as,
by way of example only, gelatin for use in an inhaler or insufflator are
formulated containing a powder mix and a suitable powder base such as
lactose or starch.

[0374]Buccal formulations include, but are not limited to, U.S. Pat. Nos.
4,229,447, 4,596,795, 4,755,386, and 5,739,136. In addition, the buccal
dosage forms described herein optionally further include a bioerodible
(hydrolysable) polymeric carrier that also serves to adhere the dosage
form to the buccal mucosa. The buccal dosage form is fabricated so as to
erode gradually over a predetermined time period. Buccal drug delivery
avoids the disadvantages encountered with oral drug administration, e.g.,
slow absorption, degradation of the active agent by fluids present in the
gastrointestinal tract and/or first-pass inactivation in the liver. The
bioerodible (hydrolysable) polymeric carrier generally comprises
hydrophilic (water-soluble and water-swellable) polymers that adhere to
the wet surface of the buccal mucosa. Examples of polymeric carriers
useful herein include acrylic acid polymers and co, e.g., those known as
"carbomers" (Carbopol®, which is obtained from B.F. Goodrich, is one
such polymer). Other components also be incorporated into the buccal
dosage forms described herein include, but are not limited to,
disintegrants, diluents, binders, lubricants, flavoring, colorants,
preservatives, and the like. For buccal or sublingual administration, the
compositions optionally take the form of tablets, lozenges, or gels
formulated in a conventional manner.

[0376]The transdermal formulations described herein include at least three
components: (1) an active agent; (2) a penetration enhancer; and (3) an
aqueous adjuvant. In addition, transdermal formulations include
components such as, but not limited to, gelling agents, creams and
ointment bases, and the like. In some embodiments, the transdermal
formulation further includes a woven or non-woven backing material to
enhance absorption and prevent the removal of the transdermal formulation
from the skin. In other embodiments, the transdermal formulations
described herein maintain a saturated or supersaturated state to promote
diffusion into the skin.

[0377]In some embodiments, formulations suitable for transdermal
administration employ transdermal delivery devices and transdermal
delivery patches and are lipophilic emulsions or buffered, aqueous
solutions, dissolved and/or dispersed in a polymer or an adhesive. Such
patches are optionally constructed for continuous, pulsatile, or on
demand delivery of pharmaceutical agents. Still further, transdermal
delivery is optionally accomplished by means of iontophoretic patches and
the like. Additionally, transdermal patches provide controlled delivery.
The rate of absorption is optionally slowed by using rate-controlling
membranes or by trapping an active agent within a polymer matrix or gel.
Conversely, absorption enhancers are used to increase absorption. An
absorption enhancer or carrier includes absorbable pharmaceutically
acceptable solvents to assist passage through the skin. For example,
transdermal devices are in the form of a bandage comprising a backing
member, a reservoir containing an active agent optionally with carriers,
optionally a rate controlling barrier to deliver a an active agent to the
skin of the host at a controlled and predetermined rate over a prolonged
period of time, and means to secure the device to the skin.

[0378]Formulations suitable for intramuscular, subcutaneous, or
intravenous injection include physiologically acceptable sterile aqueous
or non-aqueous solutions, dispersions, suspensions or emulsions, and
sterile powders for reconstitution into sterile injectable solutions or
dispersions. Examples of suitable aqueous and non-aqueous carriers,
diluents, solvents, or vehicles including water, ethanol, polyols
(propyleneglycol, polyethylene-glycol, glycerol, cremophor and the like),
suitable mixtures thereof, vegetable oils (such as olive oil) and
injectable organic esters such as ethyl oleate. Proper fluidity is
maintained, for example, by the use of a coating such as lecithin, by the
maintenance of the required particle size in the case of dispersions, and
by the use of surfactants. Formulations suitable for subcutaneous
injection also contain optional additives such as preserving, wetting,
emulsifying, and dispensing agents.

[0379]For intravenous injections, an active agent is optionally formulated
in aqueous solutions, preferably in physiologically compatible buffers
such as Hank's solution, Ringer's solution, or physiological saline
buffer. For transmucosal administration, penetrants appropriate to the
barrier to be permeated are used in the formulation. For other parenteral
injections, appropriate formulations include aqueous or nonaqueous
solutions, preferably with physiologically compatible buffers or
excipients.

[0380]Parenteral injections optionally involve bolus injection or
continuous infusion. Formulations for injection are optionally presented
in unit dosage form, e.g., in ampoules or in multi dose containers, with
an added preservative. In some embodiments, the pharmaceutical
composition described herein are in a form suitable for parenteral
injection as a sterile suspensions, solutions or emulsions in oily or
aqueous vehicles, and contain formulatory agents such as suspending,
stabilizing and/or dispersing agents. Pharmaceutical formulations for
parenteral administration include aqueous solutions of an active agent in
water soluble form. Additionally, suspensions are optionally prepared as
appropriate oily injection suspensions.

[0382]An active agent disclosed herein is also optionally formulated in
rectal compositions such as enemas, rectal gels, rectal foams, rectal
aerosols, suppositories, jelly suppositories, or retention enemas,
containing conventional suppository bases such as cocoa butter or other
glycerides, as well as synthetic polymers such as polyvinylpyrrolidone,
PEG, and the like. In suppository forms of the compositions, a
low-melting wax such as, but not limited to, a mixture of fatty acid
glycerides, optionally in combination with cocoa butter is first melted.

[0383]In some embodiments, the pharmaceutical composition described herein
is in unit dosage forms suitable for single administration of precise
dosages. In unit dosage form, the formulation is divided into unit doses
containing appropriate quantities of an active agent disclosed herein. In
some embodiments, the unit dosage is in the form of a package containing
discrete quantities of the formulation. Non-limiting examples are
packaged tablets or capsules, and powders in vials or ampoules. In some
embodiments, aqueous suspension compositions are packaged in single-dose
non-reclosable containers. Alternatively, multiple-dose reclosable
containers are used, in which case it is typical to include a
preservative in the composition. By way of example only, formulations for
parenteral injection are presented in unit dosage form, which include,
but are not limited to ampoules, or in multi dose containers, with an
added preservative.

Dosages and Administration

[0384]In some embodiments, the pharmaceutical compositions disclosed
herein are administered to an individual in need thereof. In some
embodiments, the pharmaceutical compositions disclosed herein are
administered to an individual diagnosed with (i.e., satisfies the
diagnostic criteria for) a cardiovascular disease (e.g., atherosclerosis,
angina, stenosis, restenosis, high blood pressure, an aneurysm, an
embolism, a blood clot, and/or an infarction (e.g., a myocardial
infarction or stroke). In some embodiments, the pharmaceutical
compositions disclosed herein are administered to an individual suspected
of having a cardiovascular disease. In some embodiments, the
pharmaceutical compositions disclosed herein are administered to an
individual predisposed to develop a cardiovascular disease.

[0385]In certain instances, an individual is at risk of atherosclerosis if
their c-reactive protein (CRP) levels are above about 3.0 mg/L. In
certain instances, an individual is at risk of atherosclerosis if their
homocysteine levels exceed about 15,9 mmol/L. In certain instances, an
individual is at risk of atherosclerosis if their LDL levels exceed about
160 mg/dL. In certain instances, an individual is at risk of
atherosclerosis if their HDL levels are below about 40 mg/dL. In certain
instances, an individual is at risk of atherosclerosis if their serum
creatinine levels exceed about 1.5 mg/dL. In certain instances, an
individual is pre-disposed to develop atherosclerosis if they possess the
"G" allele of SNP rs10757278 and/or the "C" allele of SNP rs1333049 both
of which are located at the locus 9p21. For disclosures regarding the "G"
allele of SNP rs10757278 and/or the "C" allele of SNP rs1333049 see
Science, Jun. 8, 2007; 316(5830):1491-93 which is herein incorporated by
reference for such disclosures. In certain instances, an individual is
pre-disposed to develop atherosclerosis if they possess LTA4H haplotypes
Hap A, HapB, HapC, HapL, HapK, and/or HapQ. For disclosures regarding
LTA4H haplotypes see International Publication No. WO/2006/105439 which
is herein incorporated by reference for such disclosures.

[0386]The daily dosages appropriate for an active agent disclosed herein
are from about 0.01 to 3 mg/kg per body weight. An indicated daily dosage
in the larger mammal, including, but not limited to, humans, is in the
range from about 0.5 mg to about 100 mg, conveniently administered in
divided doses, including, but not limited to, up to four times a day or
in extended release form. Suitable unit dosage forms for oral
administration include from about 1 to 50 mg active ingredient. The
foregoing ranges are merely suggestive, as the number of variables in
regard to an individual treatment regime is large, and considerable
excursions from these recommended values are not uncommon. Such dosages
are optionally altered depending on a number of variables, not limited to
the activity of the active agents used, the diseases or conditions to be
treated, the mode of administration, the requirements of the individual
subject, the severity of the disease or condition being treated, and the
judgment of the practitioner.

[0387]In some embodiments, administration of the cardiovascular disorder
agent results in (either partially or fully) undesired inflammation. In
some embodiments, the anti-inflammatory agent is administered to the
individual to treat the undesired inflammation. In some embodiments, the
administration of the cardiovascular agent is discontinued until the
inflamed cells and/or tissue is no longer inflamed. In some embodiments,
after the inflamed cells and/or tissue are no longer inflamed,
administration of the cardiovascular disorder agent recommences. In some
embodiments, administration of the cardiovascular agent recommences in
combination with an alternative dose of the anti-inflammatory agent.

[0388]In the case wherein the individual's condition does not improve,
upon the doctor's discretion the administration of an active agent
disclosed herein is optionally administered chronically, that is, for an
extended period of time, including throughout the duration of the
individual's life in order to ameliorate or otherwise control or limit
the symptoms of the individual's disease or condition.

[0390]Toxicity and therapeutic efficacy of such therapeutic regimens are
optionally determined in cell cultures or experimental animals,
including, but not limited to, the determination of the LD50 (the dose
lethal to 50% of the population) and the ED50 (the dose therapeutically
effective in 50% of the population). The dose ratio between the toxic and
therapeutic effects is the therapeutic index, which is expressed as the
ratio between LD50 and ED50. An active agent disclosed herein exhibiting
high therapeutic indices is preferred. The data obtained from cell
culture assays and animal studies are optionally used in formulating a
range of dosage for use in human. The dosage of such an active agent
disclosed herein lies preferably within a range of circulating
concentrations that include the ED50 with minimal toxicity. The dosage
optionally varies within this range depending upon the dosage form
employed and the route of administration utilized.

[0392]Monocyte Mono Mac 6-cells (MM6, DSMZ) are cultivated in RPMI 1640
Medium (PAA Laboratories, Pasching, Austria) with addition of 10% fetal
calf serum, 2 mM of L-glutamine (Biowhittaker), 1 mM of sodium pyruvate,
50 μg/ml of Gentamycin and 9 μg/ml of insulin (MM6 medium). The
cells are seeded with a density of 2×105/ml in 2 ml of MM6
medium in 24 well plates and are cultivated at 37 degrees C. in a
humidified atmosphere with 5% CO2 for 3 to 4 days, before they are used
for experiments.

[0396]The binding to bPF4 to RANTES (0.5 μM, recombinant human RANTES,
Peprotech, Rocky Hill, N.J., USA) or RANTES (0.5 μM) that is
preincubated with various concentrations, 0 μM, 10 μM, 50 μM and
100 μM, of the peptide of sequence SEQ ID NO: 3 per formula (3) in
HBS-EP buffer over night at room temperature is determined by means of
injection of 15 μl of the particular peptide/RANTES mixture and
observation of the binding for 180 seconds. The coupling sequence and the
measurements are carried out in a Biacore 2000 (Biacore AB) device at a
flow rate of 5 μl/min. Sensorgrams of the RANTES binding are corrected
for nonspecific background signals by means of the software BIAevaluation
3.0 (Biacore AB) and equilibrium resonance units (RU) is determined for
each injection.

Example 2

Inhibition of the Monocyte Arrest on Activated Endothelium

[0397]The interaction of monocyte Mono Mac 6 cells on activated
endothelial cells is investigated as follows: Petri dishes with confluent
HUVEC cell layers, which are activated with IL-1β, Peprotech, 10
ng/ml, 12 hours), are placed in a flow chamber. Mono Mac 6 cells
(0.5×106 cells per ml) are resuspended in properly
proportioned Hank solution (HBSS with 10 mM Hepes (Gibco BRL), pH 7.3,
0.5% bovine serum albumen (Serva) and kept on ice. Five minutes before
the experiment, there is added to the monocyte MM6 cells Ca2+ and
Mg2+ to a final concentration of 1 mM each and 60 nM of the
chemokines RANTES (Peprotech, Rocky Hill, N.J., USA) and PF4 (ChromaTec,
Greifswald) and 6 μM each of the peptides of SEQ ID NO: 2 per formula
(2), sequence SEQ ID NO: 3 per formula (3), or a control peptide and the
materials are heated to 37 degrees C. The thus pretreated cells are then
perfused across the endothelial cells at 1.5 dyn/cm3 on a microscope of
type IX 50 of the Olympus Co. The number of monocytes that are adherent
by interaction with the endothelial cells is determined after 4 minutes
in various fields by means of image analysis of pictures of a video
camera (3CCD, JVC) and recorder. The data are evaluated as mean
(n=5)±standard deviation (p<0.02) against a control.

Example 3

In Vivo Investigations in a Mouse Model of Atherosclerosis

[0398]Female ApoE-/- littermate mice 9 to 12 weeks old (The Jackson Lab,
Bar Harbor, Me., USA) will serve as the model for atherosclerosis. These
are given a fat-rich diet (21% fat: Altromin C1061) for 12 weeks. During
this time, two groups of mice receive thrice weekly intraperitoneal
injections of 50 μg of peptide of sequence SEQ ID NO: 8 per formula
(9), given below: [0399]CKEYFYTSSKSSNLAVVFVTRC (8) (SEQ ID NO: 8)(n=12
mice) or of a control peptide of sequence SEQ ID NO: 9 per formula (9),
as given below: [0400]KEYFYTSGK (9) (SEQ ID NO: 9)(n=7 mice) in saline
solution. An untreated group of mice (n=12) serve as an additional
control.

[0401]The mice are sacrificed for histological studies. During the period
of the experiment, the mice are maintained healthy. Blood samples are
taken at the start and after the end of the experimental feeding. The
leukocyte count is determined by hemocytometry and the sera are collected
and the cholesterol level is determined by means of Infinity Cholesterol
kits (Thermo Electron, Melbourne, Australia).

[0402]The extent of the atherosclerosis is determined at the aortal roots
and thoracoabdominal aortas by staining the lipid deposits with oil red O
stain (Veillard N R, Kwak B, Pelli G, Mulhaupt F, James R W, Proudfoot A
E, Mach F. Antagonism of RANTES receptors reduces atherosclerotic plaque
formation in mice. Circ Res. 2004; 94: 253-61) and is quantified by means
of computerized image analysis (Diskus software, Hilgers, Aachen).
Regions of atherosclerotic lesions are determined in 5 micron transverse
sections through heart and aortal root. The determination is done for
each aortal root by means of lipid-stained regions of 6 sections, at a
distance of 50 μm from each other. The regions of atherosclerotic
lesions re divided by the entire surface of the valve of each section.
The thoracoabdominal aorta is opened along the ventral midline and the
regions of lesions re stained in an en face preparation by means of oil
red O staining The proportion of lipid deposition is calculated as the
stained region divided by the entire thoracoabdominal surface.

Example 4

Preparation of Multi-Particulate Dosage Form

[0403]A multiparticulate dosage form is prepared. The dosage form
comprises an immediate release population of particles containing
lovastatin. The dosage form further comprises a controlled-release
population of particles comprising the peptide of SEQ ID NO: 2.

[0404]10 kg of lovastatin, 23 kg of lactose, 0.7 kg of croscarmellose
sodium, 0.7 kg polyvinylpyrrolidone K25 are blended in a high-speed
blender. The dry mixture is granulated with 4.3 kg of granulating
solution (dissolve 0.02 kg of BHA in 1.7 kg of ethanol while mixing in
the high-speed blender and add 2.6 kg of demineralized water to the
resulting solution). The granulation is dried in a bed-fluid dryer. The
dried granulation is sieved in a 0.5 mm sieve to obtain granulation
particles of the desired size.

[0405]5 mg of COR100140 26 kg of lactose, 0.8 kg of croscarmellose sodium,
0.8 kg polyvinylpyrrolidone K25 are blended in a high-speed blender. The
dry mixture is granulated with 34.3 kg of granulating solution (dissolve
0.02 kg of BHA in 1.7 kg of ethanol while mixing in the high-speed
blender and add 2.6 kg of demineralized water to the resulting solution).
The granulation is dried in a bed-fluid dryer. The dried granulation is
sieved in a 0.5 mm sieve to obtain granulation particles of the desired
size. The granules are then sprayed with a controlled release coating
composition comprising.

[0406]The immediate release granules and the controlled-release granules
are mixed together. The resulting mixture is encapsulated in gelatine
capsules.

Example 5

Preparation of a Multi-Particulate Dosage Form

[0407]10 kg Methotrexate is first screened through a suitable screen (e.g.
500 micron). 25 kg Lactose monohydrate, 8 kg hydroxypropylmethyl
cellulose, the screened methotrexate and 5 kg calcium hydrogen phosphate
(anhydrous) are then added to a suitable blender (e.g. a tumble mixer)
and blended. The blend is screened through a suitable screen (e.g. 500
micron) and reblended. About 50% of the lubricant (2.5 kg, magnesium
stearate) is screened, added to the blend and blended briefly. The blend
is roller compacted through a suitable roller compactor. The ribbon blend
is then granulated, by screening through a suitable screen (e.g. 500
micron) and reblended. The remaining lubricant (2 kg, magnesium stearate)
is screened, added to the blend and blended briefly. The granules are
screened (e.g. 200 micron) to obtain granulation particles of the desired
size.

[0408]Peptide granules are prepared by blending 2.8 kg of the peptide of
SEQ ID NO: 2 with microcrystalline cellulose (Avicel® PH101, FMC
Corp., Philadelphia, Pa.) in relative amounts of 95:5 (w/w), wet massing
the blend in a Hobart mixer with water equivalent to approximately 27% of
the weight of the blend, extruding the wet mass through a perforated
plate (Luwa EXKS-1 extruder, Fuji Paudal Co., Osaka Japan), spheronizing
the extrudate (Luwa QJ-230 marumerizer, Fuji Paudal Co.) and drying the
final granules which are about 1 mm diameter. The granules are optionally
coated with a plasticized ethylcellulose dispersion (Surelease®,
Colorcon, West Point, Pa., typically applied at 15% solids concentration)
in a bottom spray Wurster fluid bed coater (Aeromatic Strea-1, Niro Inc.,
Bubendorf, Switzerland) to obtain sustained release granules. The amount
of coating applied is varied to obtain different dissolution rate
behavior. For example, an additional coating of 2% Opadry® is
optionally applied over the Surelease® Coat.

[0409]The methotrexate immediate release granules and the peptide of SEQ
ID NO: 2 sustained release granules are mixed together and the resulting
mixture is encapsulated in gelatin capsules.

[0410]Female Harlan Sprague-Dawley mice weighing 20 to 24 g are used. The
animals used were within an age range of 6 to 8 weeks at the start of
dosing.

[0411]The mice are divided into two groups: the experimental group (n=16)
and the control group (n=16). The experimental group receives daily
intraperitoneal injections of a combination of simvastatin (80 mg/kg) and
the peptide of SEQ ID NO: 2 (1.5 mg/kg) (n=16 mice) for 14 days. The
experimental group receives daily intraperitoneal injections of a saline
solution (n=16 mice) for 14 days.

[0412]The mice are sacrificed for histological studies. Four mice from the
experimental group are sacrificed on each of days 5, 7, 12, and 14. Four
mice from the control group are sacrificed on each of days 5, 7, 12, and
14.

Necropsy and Histology

[0413]Tissue sample are taken from the (a) heart, (b) kidneys, (c) liver,
(d) stomach, and (e) muscle tissues. The sampled muscles tissues are
taken from (a) the right fore limb (the biceps femoris, extensor
digitorum longus, tibialis cranialis, and vastus medialis); (b) the left
hind limb (the biceps brachii, extensor carpi radialis longus, and flexor
carpi ulnaris); the abdominal peritoneal; the diaphragm; the masseter
superficialis; the tongue; and the trapezius).

[0414]Tissues are fixed in buffered 10% formalin, processed to wax blocks,
and then sectioned and stained with haematoxylin and eosin for
examination by light microscopy. Necrosis is graded subjectively. Minimal
necrosis is up to 10 necrotic fibers in the whole section; mild is up to
about 20% necrotic fibers; moderate is up to about 50% necrotic fibers;
and severe is more than 50% necrotic fibers.

Electron Microscopy

[0415]Samples for ultrastructural assessment are immersion fixed in 2.5%
glutaraldehyde fixative. Glutaraldehyde-fixed samples are postfixed in 1%
osmium tetroxide and processed to Araldite resin blocks. Thin, 70-90-nm
resin sections are cut and stained using uranyl acetate and lead citrate.
Ultrastructural morphology is examined with a TEM.

Muscle Histochemistry

[0416]Muscle samples are trimmed, orientated on a cork disk, and frozen in
isopentane (Fisher Scientific) pre-cooled with liquid nitrogen. Serial
cryosections of 7-μm thickness are cut from each sample for fiber
typing. Sections are stained for mATPase activity following
pre-incubation at high and low pH. One section is placed in an incubating
solution at pH 9.4 consisting of 0.5% ATP (Sigma) in 0.1 M glycine/NaCl
buffer with 0.75 M CaCl2 for 45 minutes at 37° C. A further
section is pre-incubation in 0.1 M sodium acetate buffer with 10 mM ETDA
(pH 4.1-4.3) for 10 minutes at 4° C. before placing in the
incubation solution noted previously. Following incubation the slides are
transferred to 2% CoCl2 for 5 minutes followed by 30 seconds in 10%
ammonium sulphide solution. Sections are washed thoroughly in distilled
water between each step. Sections are lightly counterstained with
Carazzi's haematoxylin before being dehydrated, cleared, and mounted in
Histomount.

Muscle Immunohistochemistry

[0417]Serial cryostat sections are stained for fast and slow myosin heavy
chains using antibodies (e.g., NCL-MHCf for fast myosin heavy chains, and
NCL-MHCs for slow myosin heavy chains). The sections are incubated in the
primary antibody for 60 minutes, then incubated in the secondary antibody
(i.e., rabbit anti-mouse HRP conjugate) for 30 minutes, before being
visualized by incubation with 3,3 diaminobenzidine tetrahydrochloride for
5 minutes. All incubations are at room temperature, and sections are
washed thoroughly in tris-buffered saline between each step. Sections are
counterstained with Carazzi's haematoxylin before being dehydrated,
cleared, and mounted in Histomount. Dewaxed sections are subjected to 2
minutes' full pressure in a microwave pressure cooker containing 0.01 M
citrate buffer at pH 6.0, and then 5 minutes' digestion at room
temperature by proteinase K. Endogenous peroxidase activity is blocked by
incubation in a peroxidase inhibitor for 20 minutes, followed by 15
minutes in 20% normal rabbit serum. Mouse monoclonal antibody is applied
for 30 minutes, followed by 30 minutes in peroxidase-conjugated rabbit
anti-mouse antibody. Vector Laboratory's SG peroxidase substrate kit
(SK4700) is then applied for 10 minutes. Following an additional 15
minutes of incubation in 20% normal rabbit serum, a mouse mAB to fast
myosin is applied. This is visualized using Vector Red alkaline
phosphatase substrate kit (Vector Labs SK5100) for 10 minutes. All
incubations were at room temperature, and sections are washed thoroughly
in tris-buffered saline between each step. Sections are dehydrated,
cleared, and mounted in Histomount.

[0418]Female ApoE-/- littermate mice 9 to 12 weeks old (The Jackson Lab,
Bar Harbor, Me., USA) will serve as the model for atherosclerosis. These
are given a fat-rich diet (21% fat; Altromin C1061) for 12 weeks. During
this time, two groups of mice receive thrice weekly intraperitoneal
injections of a combination of simvastatin (5 mL/kg) and the peptide of
SEQ ID NO: 2 (1.5 mg/kg) (n=12 mice) or a saline solution (n=7 mice).

[0419]The mice are sacrificed for histological studies. During the period
of the experiment, the mice are maintained healthy. Blood samples are
taken at the start and after the end of the experimental feeding. The
leukocyte count is determined by hemocytometry and the sera are collected
and the cholesterol level is determined by means of Infinity Cholesterol
kits (Thermo Electron, Melbourne, Australia).

[0420]The extent of the atherosclerosis is determined at the aortal roots
and thoracoabdominal aortas by staining the lipid deposits with oil red O
stain (Veillard N R, Kwak B, Pelli G, Mulhaupt F, James R W, Proudfoot A
E, Mach F. Antagonism of RANTES receptors reduces atherosclerotic plaque
formation in mice. Circ Res. 2004; 94: 253-61) and is quantified by means
of computerized image analysis (Diskus software, Hilgers, Aachen).
Regions of atherosclerotic lesions are determined in 5 micron transverse
sections through heart and aortal root. The determination is done for
each aortal root by means of lipid-stained regions of 6 sections, at a
distance of 50 μm from each other. The regions of atherosclerotic
lesions re divided by the entire surface of the valve of each section.
The thoracoabdominal aorta is opened along the ventral midline and the
regions of lesions re stained in an en face preparation by means of oil
red O staining The proportion of lipid deposition is calculated as the
stained region divided by the entire thoracoabdominal surface.

Example 8

Human Clinical Trial of P4/RANTES Antagonist in Combination with
Torcetrapib as a Treatment for Hypercholesterolemia

[0421]Study Objective(s): The primary objective of this study is to assess
the efficacy of a combination of torcetrapib and the peptide of SEQ ID
NO: 2 (C-KEYFYTSGKCSNPAVVFVTR-C) (T/P2; 60 mg/1.5 mg/kg) in subjects with
homozygous familial hypercholesterolemia (HoFH) versus torcetrapib (60
mg) alone.

Methods

[0422]Study Design: This study is a prospective, double-blind,
multicenter, parallel-treatment trial comparing T/P2 versus T alone in
male and female subjects≧18 years of age with HoFH. After initial
screening, eligible subjects enter a 4-week screening period, consisting
of 2 visits (Weeks-4 and -1), during which all lipid-lowering drugs are
discontinued (except for bile acid sequestrants and cholesterol
absorption inhibitors) and therapeutic lifestyle change counseling (TLC)
according to National Cholesterol Education Program (NCEP) Adult
Treatment Panel (ATP-III) clinical guidelines or equivalent is initiated.
Subjects already on apheresis continue their treatment regimen
maintaining consistent conditions and intervals during the study. At
Visit 3 (Week 0), subjects begin treatment with the T/P2 fixed
combination once daily (QD) for 6 weeks or T alone. Final visit (Visit 6)
occurs at Week 18. Study visits are timed with subjects' apheresis
treatments to occur immediately before the visit procedures, where
applicable. When the intervals between aphereses are misaligned with a
study drug treatment period, the subjects are kept in the same drug
treatment period until the next scheduled apheresis, and until the
intervals are brought back to the original length of time. Efficacy
measures are done at least 2 weeks after the previous apheresis and just
before the apheresis procedure scheduled for the day of study visit.

[0423]Number of Subjects: 50 subjects divided into two groups-the
experimental group (n=25) and the control group (n=25).

[0424]Diagnosis and Main Criteria for Inclusion: Men and women 18 years of
age or older with definite evidence of the familial hypercholesterolemia
(FH) homozygote per World Health Organization guidelines, and with serum
fasting triglyceride (TG)≦400 mg/dL (4.52 mmol/L) for subjects
aged>20 years and 200 mg/dL (2.26 mmol/L) for subjects aged 18-20
years, are screened for study participation.

[0425]Study Treatment: Subjects are randomized into two groups. During the
three 6-week treatment period, subjects in the experimental group take 1
tablet of T/P2 QD, with food, immediately after the morning meal.
Subjects in the control group take 1 tablet of T QD, with food,
immediately after the morning meal.

[0426]Efficacy Evaluations: The primary endpoints are the mean percent
changes in HDL-C and LDL-C from baseline to the end of each treatment
period (ie, Weeks 6, 12 and 18). A lipid profile which included HDL-C and
LDL-C is obtained at each study visit.

[0427]Safety Evaluations: Safety is assessed using routine clinical
laboratory evaluations (hematology and urinalysis panels at Weeks-4, 0
and 18, and chemistry also at Weeks 6 and 12). Vital signs are monitored
at every visit, and physical examinations and electrocardiograms (ECGs)
are performed at Weeks 0 and 18. Urine pregnancy testing is carried out
at every visit except Week-1. Subjects are monitored for adverse events
(AEs) from Week 0 to Week 18. Week 18 safety assessments are completed at
early termination if this took place.

[0428]Statistical Methods: The primary efficacy endpoints are the percent
changes in HDL-C and LDL-C from baseline to the end of each treatment
period (ie, Weeks 6, 12, and 18). The primary efficacy analysis
population is the full analysis set (FAS) which includes all subjects who
received at least 1 dose of study drug and had both a baseline and at
least 1 valid post-baseline measurement at each analysis period.

[0429]The primary efficacy endpoints are analyzed through the computation
of sample means of percent (or nominal) changes, their 95% confidence
intervals (CIs), 1-sample t-test statistics, and corresponding p-values.
Incremental treatment differences between different dose levels are also
estimated and 95% CIs obtained. Hypothesis testing is 2-sided with an
overall family-wise type I error rate of 5% (ie, p=0.05 significance
level). Hochberg's procedure is used to control the family-wise error
rate for multiple comparisons.

Example 9

Human Clinical Trial of MIF Antagonist in Combination with Atorvastatin as
a Treatment for Atherosclerosis

[0430]Study Objective(s): To measure the effect of 18 months of treatment
with lipid lowering treatment (atorvastatin 80-mg daily) versus 8 months
of treatment with atorvastatin in combination with a peptide of SEQ ID
NO: 2 (1.5 mg/kg) on coronary artery plaque using intravascular
ultrasound (IVUS) imaging of the coronary arteries.

[0436]Approximately 400 subjects (200 subjects per treatment group) are to
be enrolled

Diagnosis and Main Criteria for Inclusion:

[0437]Male and female subjects between 30-75 years of age with CAD who
have had a coronary catheterization. Precise angiographic inclusion
criteria will determine subject eligibility, specifically the presence of
at least one obstruction in a major cardiac vessel with at least a 20%
luminal diameter narrowing by visual estimation. In addition, subjects
must have had a "target vessel" for IVUS interrogation with no more than
50% luminal narrowing throughout a segment that was a minimum of 30 mm in
length (the "target segment"). The target vessel must not have undergone
previous intervention, nor have been a candidate for intervention at the
time of Baseline catheterization. Lipid entry criterion require subjects
to have a low-density lipoprotein cholesterol (LDL-C) between 125 and 210
mg/dL following a 4- to 10-week washout period if the subject is taking
antihyperlipidemic medication.

Study Treatment:

[0438]Subjects are divided into the groups. The first group (n=200)
receives atorvastatin. The second group (n=200) receives atorvastatin in
combination with a peptide of SEQ ID NO: 2 (1.5 mg/kg).

[0439]Placebo Run-in Period: Subjects in the two groups are instructed to
take two placebo tablets at bedtime each day and return to the Clinic in
two weeks for the Randomization Visit. The time between visits during the
Placebo Run-in Period is not to exceed 17 days. Subjects are also
required to be at least 90% compliant before randomization to the
double-blind period.

[0440]Double-Blind Period: Subjects in group 1 are instructed to take
80-mg atorvastatin (2×40-mg tablet) and one placebo tablet daily at
bedtime each day for 18 months. Subjects in group 2 are instructed to
take 80-mg atorvastatin (2×40-mg tablet) in combination with a
peptide of SEQ ID NO: 2 (1.5 mg/kg; 1 tablet) daily at bedtime each day
for 18 months.

Efficacy Evaluations:

[0441]Primary efficacy variable: The percent change in total plaque volume
for all slices of anatomically comparable segments of the target coronary
artery from Baseline to Month 18 measured by IVUS.

[0442]Safety Evaluations: Safety of the treatment is assessed by an
evaluation of type, frequency, intensity, and duration of all reported
adverse events (AEs), monitoring of laboratory parameters, and changes in
vital signs. Data for electrocardiogram (ECG) results and physical
examination findings is collected.

Example 10

In Vivo Investigations in a Rat Model of Arthritis Disease to Test
Combination of Etanercept and the Peptide of SEQ ID NO: 2

[0443]31 Male Lewis rats are immunized with complete Freund's adjuvant on
day 0 to induce an aggressive arthritis characterized by joint
destruction and paw swelling.

[0444]From day 8 to 20, two groups of rats receive thrice weekly
intraperitoneal injections of 50 μg of peptide of SEQ ID NO: 3 (n=12
rats). During this time, the rats also receive weekly subcutaneous
injections of 50 μg Etanercept. An untreated group of rats (n=12)
serve as a control.

[0445]Every week, paw swelling is determined by water displacement
plethysmometry. The extent of arthritis is determined at the end of the
study on day 21. Radiographs are obtained of the right hind paw to assess
bone changes using a semi-quantitative scoring system: demineralization
(0-2+), calcaneal erosion (0-1+), and heterotropic bone formation (0-1+),
with a maximum possible score=6. Blood samples are tested for
neutropenia.

Example 11

In Vivo Investigations in a Rat Model of Crohn's Disease to Test
Combination of Methotrexate and the Peptide of SEQ ID NO: 2

[0446]A modified animal model disclosed in Kirkil, C. et al., J
Gastrointest Surg. 2008, 12, 1429-35 is used. Twenty-eight Sprague-Dawley
rats are divided into four groups. Groups I and II are used as
sham-operated and control groups, respectively. Bowel inflammation is
induced by intrajejunal injection of iodoacetamide in groups III and IV.
Rats in group IV are treated with oral preparation of methotrexate (10
mg) and intravenous injection of 50 μg of peptide of sequence SEQ ID
NO: 3 (n=12 rats).

[0447]Three days after induction of the inflammation, partial resection of
test loop and anastomosis is performed. Re-laparotomy is performed,
anastomosis bursting pressures and peritonitis scores are measured, and
tissue samples are obtained for the measurements of tissue
hydroxylproline level and mucosal damage index 4 days later.

[0448]On the fourth day, measurements of tissue hydroxylproline level and
mucosal damage index are obtained. The severity of iodoacetamide induced
intestinal inflammation, wound healing in the inflamed intestinal tissue,
and decrease in severity of peritonitis is also recorded.

Example 12

Human Clinical Trial in SLE to Test Combination of Cyclophosphamide and
the Peptide of SEQ ID NO: 2

[0449]Study Objective(s): The primary objective of this study is to assess
efficacy of the fixed combination cyclophosphamide and the peptide of SEQ
ID NO: 2 (C/P2; 60/20 mg, 60/40 mg, 60/80 mg) in subjects with systemic
lupus erythematosus (SLE) who are currently receiving cyclophosphamide.
This study will also determine if P2 is effective in decreasing disease
activity in these patients.

Methods

[0450]The first part of the study is a dose-escalation study in which
participants will receive one of two doses of P2 (20 mg, or 40 mg,); this
part of the study will last 60 days. At screening, patients will have an
IV catheter inserted into their arms for administration of
cyclophosphamide and P2. Patients will also have medical and medication
history assessments, a comprehensive physical exam, and blood and urine
tests. There are 5 study visits for the first part of the trial; these
will occur at screening, at study entry, and Days 1, 14, and 28. Selected
visits will include physical exam, vital signs measurement, blood and
urine tests, and disease activity assessment. At Days 7 and 60, patients
will be contacted by phone to report their medication history and any
adverse effects they have experienced.

[0451]The second part of the study will evaluate a single 80 mg dose of
P2; this part of the study will last 90 days. In the study, participants
will be randomly assigned to one of two groups. At the start of the
study, Group 1 participants will receive P2 and cyclophosphamide and
Group 2 participants will receive cyclophosphamide only. There will be 9
study visits; these will occur at study screening, study entry, and Days
1, 4, 7, 14, 28, and 60. At selected visits, patients will undergo
physical exam, vital signs measurement, blood tests and urine tests, and
disease activity assessment.

[0452]Number of Subjects: It is planned to recruit between 30 and 50
subjects for each part of the study.

[0453]Diagnosis and Main Criteria for Inclusion: Diagnosis of SLE by
American College of Rheumatology (ACR) criteria

[0454]Concurrent treatment with intravenous cyclophosphamide for at least
one of the following manifestations of lupus: World Health Organization
(WHO) class III, IV, or V lupus nephritis; British Isles Lupus Assessment
Group (BILAG) score of A for vasculitis; BILAG score of A for cytopenia;
BILAG score of A for nervous system; Stable medication regimen for at
least 4 weeks prior to study entry; Weight between 40 kg (88.2 lbs) and
125 kg (275.6 lb).

[0455]Study Treatment: During the study periods, subjects will have an IV
catheter inserted into their arms for intravenous bi-weekly
administration of cyclophosphamide and P2.

Human Clinical Trial in Rheumatoid Arthritis to Test Combination of
Infliximab and the Peptide of SEQ ID NO: 2

[0458]Study Objective(s): The primary objective of this study is to assess
efficacy of the fixed combination infliximab/The peptide of SEQ ID NO: 2
(I/P2; 5 mg/kg/20 mg, 10 mg/kg/20 mg, 15 mg/kg/20 mg) in subjects with
rheumatoid arthritis who are currently receiving infliximab for treatment
of rheumatoid arthritis. This study will also determine if P2 is
effective in decreasing disease activity in these patients.

Methods

[0459]Participants will receive nine infusions of infliximab and P2 every
three weeks during this 28-week study. The drug is given intravenously
(IV, into a vein) over 2 hours. The first three infusions will be at a
dose of 5 mg/kg of body weight. Patients will also receive 20 mg P2 in a
saline solution (IV, into a vein) over 1 hour. Patients who improve on
this regimen will receive another 6 infusions at the same dose. Patients
who do not significantly improve on 5 mg/kg at the end of 6 weeks (the
third infusion) may continue with phase 2 of the study, in which they
will be randomly assigned to receive either: 1) 6 additional doses of
tinfliximab at 5 mg/kg per dose, or 2) a gradually increased dose of
inflilximab to a maximum of 15 mg/kg. In addition, all patients will
continue to take P2 at the same dose as when they entered the study.

[0460]Patients will have imaging studies (x-rays, MRI and Dexa scan) at
the beginning and end of the study and will collect a 24-hour urine
sample before each infliximab and P2 infusion.

[0461]Number of Subjects: It is planned to recruit between 30 and 50
subjects for each part of the study.

[0462]Inclusion criteria: Patients must be at least 18 years old at the
screening visit. Patients must have a diagnosis of adult-onset RA of at
least six months duration but not longer than fifteen years as defined by
the 1987 American College of Rheumatology classification criteria.

[0463]Patients must have active RA disease as defined by: 9 tender joints
at Screening and Baseline, 9 swollen joints at Screening and Baseline.
and fulfilling 1 of the following 2 criteria during the screening period,
30 mm/hour ESR (Westergren), or CRP>15 mg/L.

[0464]Patients must have received treatment with infliximab for at least 6
months prior to the Baseline visit. The dose of infliximab and route of
administration must have been stable for at least 2 months prior to the
baseline visit. The minimum stable dose of infliximab allowed is 5 mg/kg
weekly.

[0465]Exclusion criteria: Patients must not have a diagnosis of any other
inflammatory arthritis (e.g., psoriatic arthritis or ankylosing
spondylitis), Patients must not have a secondary, non-inflammatory type
of arthritis (e.g. OA or fibromyalgia), Female patients who are breast
feeding, pregnant, or plan to become pregnant during the trial or for
three months following last dose of study drug, Patients with a history
of tuberculosis or positive chest X-ray for tuberculosis or positive,
Patients at a high risk of infection (e.g. leg ulcers, indwelling urinary
catheter and persistent or recurrent chest infections and patients who
are permanently bed ridden or wheelchair bound), Patients with known
human immunodeficiency virus (HIV) infection, Patients with an active
malignancy of any type or a history of malignancy (except basal cell
carcinoma of the skin that has been excised prior to study start),
Patients with a current or recent history, as determined by the
Investigator, of severe, progressive, and/or uncontrolled renal, hepatic,
hematological, gastrointestinal, endocrine, pulmonary, cardiac,
neurological, or cerebral disease which would interfere with the
patient's participation in the trial, Patients with a history of, or
suspected, demyelinating disease of the central nervous system (e.g.
multiple sclerosis or optic neuritis).

[0466]Primary Outcome measures: Compare efficacy of two dose regimens of
infliximab in combination with P2 to infliximab alone in patients with RA
measured by the ACR20 at week 28.

[0467]Secondary outcome measures: Assess Safety and Tolerability of two
dose regimens of infliximab in combination with P2 and infliximab alone
in patients with RA; prevention of joint damage in patients with RA;
Health Outcomes Measures

[0468]Study treatment: During the study periods, subjects will have an IV
catheter inserted into their arms for intravenous administration of
infliximab and P2.

[0471]While preferred embodiments of the present invention have been shown
and described herein, it will be obvious to those skilled in the art that
such embodiments are provided by way of example only. Numerous
variations, changes, and substitutions will now occur to those skilled in
the art without departing from the invention. It should be understood
that various alternatives to the embodiments of the invention described
herein may be employed in practicing the invention. It is intended that
the following claims define the scope of the invention and that methods
and structures within the scope of these claims and their equivalents be
covered thereby.